Agent for improving learning or memory

ABSTRACT

Disclosed is an agent for improving learning and/or memory, which is useful for therapy of dementia accompanying disorder of memory due to a cerebrovascular disease, neurodegenerative disease such as Alzheimer&#39;s disease, endocrine disease, nutritional or metabolic disorder, infectious disease, drug addiction or the like. The agent for improving learning and/or memory according to the present invention comprises as an effective ingredient an isoquinoline derivative having a specific structure, such as (4aR, 12aR)-2-methyl-4a-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a-octahydro-quinoline[2,3-g]isoquinoline or a pharmaceutically acceptable salt thereof.

This application is the national phase under 35 U.S.C. §371 of PCT International Application No. PCT/JP00/08847 which has an International filing date of Nov. 30, 2000, which designated the United States of America.

TECHNICAL FIELD

The present invention relates to an agent for improving learning and/or memory comprising as an effective ingredient a quinolinoisoquinoline derivative or a pharmaceutically acceptable acid addition salt thereof.

BACKGROUND ART

Learning means to acquire change in behavior, which continues for a relatively long time, which is caused by experience or practice, or the process for acquiring the change in behavior. Memory means to retain information for a certain time, which information is obtained through experience, and to retrieve the information as required. However, the definitions of these two concepts are not simple, and are not independent for each other but most of them overlap. Therefore, learning ability and mneme are often measured by similar experiments in the field of behavioral pharmacology.

Learning includes the steps of encoding, storage, recognition and retrieval. Even if one of these steps is inhibited, disorder of memory occurs (Seiden, L. S. & Dykstra, L. A., Psychopharmacology, a biochemical and behavioral approach. Van Nostrand Reinhold Co., New York(1077)). A representative disease accompanying memory disorder and/or learning disability is dementia. The term “dementia” means the continuous state in which the intellectual ability is reduced, which intellectual ability had ever developed to the normal level. Symptoms of dementia include, in addition to memory disorder and/or learning disability, mood disorder, emotional disorder, intellectual disturbance and psychomotor disturbance. Improvement of memory disorder which likely to cause serious problems in social life is an indispensable action of anti-dementia drugs.

In the brains of patients suffering from senile dementia or Alzheimer's disease, remarkable reduction in neurotransmitters and biosynthesis enzymes thereof is observed. Therefore, therapy by drugs such as dopamine, noradrenalin, serotonin, acetylcholine and GABA, which act on the transmission process through neurotransmitters is drawing attention. Since it is known that the hypofunction of acetylcholine system is prominent in brains of patients suffering from dementia, the current mainstream of development of therapeutic method for dementia is the development of drugs targeting the activation of acetylcholine nervous system. An anti-dementia drug, tacrine, which has obtained approval, is an acetylcholinesterase inhibitor, and it has been confirmed that improvement of intellectual function to a certain degree is observed in about half of the cases in which the drug is administered. However, this drug has a problem in the hepatic toxicity and choline-related side effects. With Aricept effective for Alzheimer's disease through the similar mechanism, improvement is observed in about half cases for patients suffering from the dementia in light to medium degree.

On the other hand, references disclosing quinolinoisoquinoline derivatives include Japanese Laid-open Patent Application (Kokai) No. 4-275288, WO93/01186 and WO99/02157. These patent literatures disclose the uses of the derivatives as immunosuppressive agents, analgesics and antitussives. However, these references are totally silent about improvement of learning or memory.

DISCLOSURE OF THE INVENTION

The present inventors intensively studied to discover that specific isoquinoline derivatives exhibit excellent effect for improving learning and/or memory, thereby completing the present invention.

That is, the present invention provides an agent for improving learning and/or memory comprising as an effective ingredient an isoquinoline derivative of the Formula (I):

{wherein R¹ represents hydrogen, C₁-C₅ alkyl, C₄-C₇ cycloalkylalkyl, C₅-C₇ cycloalkenylalkyl, C₇-C₁₄ aralkyl, C₄-C₅ transalkenyl, allyl, furanyl-2-ylalkyl, thienyl-2-ylalkyl, C₁-C₅ alkanoyl, benzoyl, vinyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl or C₈-C₁₄ arylalkanoyl; R² represents hydrogen or OR⁶ (wherein R⁶ represents hydrogen, C₁-C₅ alkyl or C₁-C₅ alkanoyl); R³ and R^(3′) independently represent C₁-C₅ alkyl, hydrogen, chlorine, fluorine, bromine, iodine, trifluoromethyl, cyano, hydroxy, C₁-C₃ alkoxycarbonyl, C₁-C₃ alkylcarbonylamino, C₁-C₅ alkoxy, nitro, amino, or C₁-C₃ alkylamino; R⁴ represents hydrogen, hydroxy, C₁-C₃ alkoxy, benzyl, or C₁-C₅ alkanoyl or halogen; X represents nitrogen or carbon; R⁵ exists only when X is carbon, and represents C₁-C₅ alkyl, hydrogen, chlorine, fluorine, bromine, iodine, trifluoromethyl, cyano, hydroxy, C₁-C₃ alkoxycarbonyl, C₁-C₃ alkylcarbonylamino, C₁-C₅ alkoxy, nitro, amino or C₁-C₃ alkylamino}

or a pharmaceutically acceptable salt thereof. The present invention also provides a use of said isoquinoline derivative represented by the above-described Formula (I) or the pharmaceutically acceptable salt thereof for the preparation of an agent for improving learning and/or memory. The present invention further provides a method for improving learning and/or memory comprising administering an effective amount of the isoquinoline derivative represented by the above-described Formula (I) or the pharmaceutically acceptable salt thereof.

By the present invention, an agent for improving learning and/or memory was provided, which is useful for therapy of dementia accompanying memory disorder due to a cerebrovascular disease, neurodegenerative disease such as Alzheimer's disease, endocrine disease, nutritional or metabolic disorder, infectious disease, drug addiction or the like.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the learning process of the rats to which Compound 1 that is the agent for improving learning and/or memory according to the present invention, in comparison with the learning process of the rats to which saline was administered.

FIG. 2 shows the Step-Down latency of the group of mice to which MK-801 that is a compound inducing learning disability and memory disorder was administered and then Compound 1 which is the agent for improving learning and/or memory according to the present invention was administered, in comparison with the Step-Down latency of the group to which the solvent alone was administered and the Step-Down latency of the group to which MK-801 alone was administered.

FIG. 3 shows the learning process of the rats to which Compound 8 that is the agent for improving learning and/or memory according to the present invention, in comparison with the learning process of the rats to which saline was administered.

BEST MODE FOR CARRYING OUT THE INVENTION

Preferred modes of the agent for improving learning and/or memory comprising the isoquinoline derivative of the Formula (I) or a pharmaceutically acceptable acid addition salt thereof, according to the present invention, are as follows:

R¹ is preferably hydrogen, C₁-C₅ alkyl, C₄-C₇ cycloalkylalkyl, C₅-C₇ cycloalkenylalkyl, C₇-C₁₄ aralkyl, C₄-C₅ transalkenyl, allyl, furanyl-2-ylalkyl, thienyl-2-ylalkyl, C₁-C₅ alkanoyl, benzoyl, vinyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl or C₈-C₁₄ arylalkanoyl, and especially preferably hydrogen, methyl, ethyl, cyclopropylmethyl, allyl, phenethyl, furan-2-ylethyl or thiophene-2-ylethyl.

R² is preferably hydrogen or OR⁶ (wherein R⁶ represents hydrogen, C₁-C₅ alkyl or C₁-C₅ alkanoyl), especially preferably hydrogen, hydroxy, methoxy or ethoxy.

R³ and R^(3′) independently are preferably C₁-C₅ alkyl, hydrogen, chlorine, fluorine, bromine, iodine, trifluoromethyl, cyano, hydroxy, C₁-C₃ alkoxycarbonyl, C₁-C₃ alkylcarbonylamino, C₁-C₅ alkoxy, nitro, amino or C₁-C₃ alkylamino, and especially preferably are methyl, hydrogen, chlorine, fluorine, bromine, iodine, hydroxy, methoxy, nitro, amino or dimethylamino.

R⁴ is preferably hydrogen, hydroxy, C₁-C₃ alkoxy, benzyl, C₁-C₅ alkanoyl or halogen, and especially preferably hydrogen, hydroxy or methoxy.

X represents nitrogen or carbon. R⁵ exists only when X is carbon, and is preferably C₁-C₅ alkyl, hydrogen, chlorine, fluorine, bromine, iodine, trifluoromethyl, cyano, hydroxy, C₁-C₃ alkoxycarbonyl, C₁-C₃ alkylcarbonylamino, C₁-C₅ alkoxy, nitro, amino or C₁-C₃ alkylamino, and especially preferably methyl, hydrogen, chlorine, fluorine, bromine, iodine, hydroxy, methoxy, nitro, amino or dimethylamino. Needless to say, the compounds of the present invention are not restricted to those mentioned above.

Formula (I) represents relative configuration of the compounds and includes racemic compound and optically active compounds of which absolute structures are represented by the following Formulae (A) and (B). Among these, the optically active compounds represented by the following Formulae (A) are preferred.

Examples of preferred pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid salt, sulfuric acid salt, nitric acid salt, hydrobromic acid salt, hydroiodic acid salt and phosphoric acid salt; organic carboxylic acid salts such as acetic acid salt, lactic acid salt, citric acid salt, oxalic acid salt, glutaric acid salt, malic acid salt, tartaric acid salt, fumaric acid salt, mandelic acid salt, maleic acid salt, benzoic acid salt and phthalic acid salt; and organic sulfonic acid salts such as methanesulfonic acid salt, ethanesulfonic acid salt, benzenesulfonic acid salt, p-toluenesulfonic acid salt and camphorsulfonic acid salt. Among these, hydrochloric acid, hydrobromic acid, phosphoric acid salt, tartaric acid salt, methanesulfonic acid salt and the like are especially preferred, but the pharmaceutically acceptable salts are not restricted to those mentioned above.

The compounds used in the present invention also include the novel compounds represented by Formula (II) below.

{(A) wherein R¹ represents hydrogen, C₁-C₅ alkyl, C₄-C₇ cycloalkylalkyl, C₅-C₇ cycloalkenylalkyl, C₇-C₁₄ aralkyl, C₄-C₅ transalkenyl, allyl, furanyl-2-ylalkyl, thienyl-2-ylalkyl, C₁-C₅ alkanoyl, benzoyl, vinyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl or C₈-C₁₄ arylalkanoyl; R² represents hydrogen or OR⁶ (wherein R⁶ represents hydrogen, C₁-C₅ alkyl or C₁-C₅ alkanoyl); R³ and R^(3′) independently represent C₁-C₅ alkyl, chlorine, fluorine, bromine, iodine, trifluoromethyl, cyano, hydroxy, C₁-C₃ alkoxycarbonyl, C₁-C₃ alkylcarbonylamino, C₁-C₅ alkoxy, nitro, amino or C₁-C₃ alkylamino; R⁴ represents hydrogen or C₁-C₃ alkyl; R⁵ represents C₁-C₅ alkyl, chlorine, fluorine, bromine, iodine, trifluoromethyl, cyano, hydroxy, C₁-C₃ alkoxycarbonyl, C₁-C₃ alkylcarbonylamino, C₁-C₅ alkoxy, nitro, amino or C₁-C₃ alkylamino; or

(B) wherein R¹ represents hydrogen, thienyl-2-ylalkyl, C₁-C₅ alkanoyl, benzoyl, vinyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl or C₈-C₁₄ arylalkanoyl; R² represents hydrogen or OR⁶ (wherein R⁶ represents hydrogen, C₁-C₅ alkyl or C₁-C₅ alkanoyl); R³ and R^(3′) independently represent C₁-C₅ alkyl, hydrogen, chlorine, fluorine, bromine, iodine, trifluoromethyl, cyano, hydroxy, C₁-C₃ alkoxycarbonyl, C₁-C₃ alkylcarbonylamino, C₁-C₅ alkoxy, nitro, amino or C₁-C₃ alkylamino; R⁴ represents hydrogen or C₁-C₃ alkyl; and R⁵ represents C₁-C₅ alkyl, chlorine, fluorine, bromine, iodine, trifluoromethyl, cyano, hydroxy, C₁-C₃ alkoxycarbonyl, C₁-C₃ alkylcarbonylamino, C₁-C₅ alkoxy, nitro, amino or C₁-C₃ alkylamino}.

Specific examples of the compounds represented by Formula (II) are shown in Tables 1 to 52.

TABLE 1 Compound No. R1 R2 R3 R3′ R4 R5 1 Me H Cl 5-Cl H Me 2 Me H Cl 5-Cl H NH2 3 Me H Cl 5-Cl H OH 4 Me H Cl 5-Cl Me Me 5 Me H Cl 5-Cl Me NH2 6 Me H Cl 5-Cl Me OH 7 Me H Cl 6-Cl H Me 8 Me H Cl 6-Cl H NH2 9 Me H Cl 6-Cl H OH 10 Me H Cl 6-Cl Me Me 11 Me H Cl 6-Cl Me NH2 12 Me H Cl 6-Cl Me OH 13 Me H Cl 7-Cl H Me 14 Me H Cl 7-Cl H NH2 15 Me H Cl 7-Cl H OH 16 Me H Cl 7-Cl Me Me 17 Me H Cl 7-Cl Me NH2 18 Me H Cl 7-Cl Me OH 19 Me H Cl 5-NH2 H Me 20 Me H Cl 5-NH2 H NH2 21 Me H Cl 5-NH2 H OH 22 Me H Cl 5-NH2 Me Me 23 Me H Cl 5-NH2 Me NH2 24 Me H Cl 5-NH2 Me OH 25 Me H Cl 6-NH2 H Me 26 Me H Cl 6-NH2 H NH2 27 Me H Cl 6-NH2 H OH 28 Me H Cl 6-NH2 Me Me 29 Me H Cl 6-NH2 Me NH2 30 Me H Cl 6-NH2 Me OH 31 Me H Cl 7-NH2 H Me 32 Me H Cl 7-NH2 H NH2 33 Me H Cl 7-NH2 H OH 34 Me H Cl 7-NH2 Me Me 35 Me H Cl 7-NH2 Me NH2 36 Me H Cl 7-NH2 Me OH 37 Me H Cl 5-Me H Me 38 Me H Cl 5-Me H NH2 39 Me H Cl 5-Me H OH 40 Me H Cl 5-Me Me Me

TABLE 2 Compound No. R1 R2 R3 R3′ R4 R5 41 Me H Cl 5-Me Me NH2 42 Me H Cl 5-Me Me OH 43 Me H Cl 6-Me H Me 44 Me H Cl 6-Me H NH2 45 Me H Cl 6-Me H OH 46 Me H Cl 6-Me Me Me 47 Me H Cl 6-Me Me NH2 48 Me H Cl 6-Me Me OH 49 Me H Cl 7-Me H Me 50 Me H Cl 7-Me H NH2 51 Me H Cl 7-Me H OH 52 Me H Cl 7-Me Me Me 53 Me H Cl 7-Me Me NH2 54 Me H Cl 7-Me Me OH 55 Me H NH2 5-Cl H Me 56 Me H NH2 5-Cl H NH2 57 Me H NH2 5-Cl H OH 58 Me H NH2 5-Cl Me Me 59 Me H NH2 5-Cl Me NH2 60 Me H NH2 5-Cl Me OH 61 Me H NH2 6-Cl H Me 62 Me H NH2 6-Cl H NH2 63 Me H NH2 6-Cl H OH 64 Me H NH2 6-Cl Me Me 65 Me H NH2 6-Cl Me NH2 66 Me H NH2 6-Cl Me OH 67 Me H NH2 7-Cl H Me 68 Me H NH2 7-Cl H NH2 69 Me H NH2 7-Cl H OH 70 Me H NH2 7-Cl Me Me 71 Me H NH2 7-Cl Me NH2 72 Me H NH2 7-Cl Me OH 73 Me H NH2 5-NH2 H Me 74 Me H NH2 5-NH2 H NH2 75 Me H NH2 5-NH2 H OH 76 Me H NH2 5-NH2 Me Me 77 Me H NH2 5-NH2 Me NH2 78 Me H NH2 5-NH2 Me OH 79 Me H NH2 6-NH2 H Me 80 Me H NH2 6-NH2 H NH2

TABLE 3 Compound No. R1 R2 R3 R3′ R4 R5 81 Me H NH2 6-NH2 H OH 82 Me H NH2 6-NH2 Me Me 83 Me H NH2 6-NH2 Me NH2 84 Me H NH2 6-NH2 Me OH 85 Me H NH2 7-NH2 H Me 86 Me H NH2 7-NH2 H NH2 87 Me H NH2 7-NH2 H OH 88 Me H NH2 7-NH2 Me Me 89 Me H NH2 7-NH2 Me NH2 90 Me H NH2 7-NH2 Me OH 91 Me H NH2 5-Me H Me 92 Me H NH2 5-Me H NH2 93 Me H NH2 5-Me H OH 94 Me H NH2 5-Me Me Me 95 Me H NH2 5-Me Me NH2 96 Me H NH2 5-Me Me OH 97 Me H NH2 6-Me H Me 98 Me H NH2 6-Me H NH2 99 Me H NH2 6-Me H OH 100 Me H NH2 6-Me Me Me 101 Me H NH2 6-Me Me NH2 102 Me H NH2 6-Me Me OH 103 Me H NH2 7-Me H Me 104 Me H NH2 7-Me H NH2 105 Me H NH2 7-Me H OH 106 Me H NH2 7-Me Me Me 107 Me H NH2 7-Me Me NH2 108 Me H NH2 7-Me Me OH 109 Me H Me 5-Cl H Me 110 Me H Me 5-Cl H NH2 111 Me H Me 5-Cl H OH 112 Me H Me 5-Cl Me Me 113 Me H Me 5-Cl Me NH2 114 Me H Me 5-Cl Me OH 115 Me H Me 6-Cl H Me 116 Me H Me 6-Cl H NH2 117 Me H Me 6-Cl H OH 118 Me H Me 6-Cl Me Me 119 Me H Me 6-Cl Me NH2 120 Me H Me 6-Cl Me OH

TABLE 4 Compound No. R1 R2 R3 R3′ R4 R5 121 Me H Me 7-Cl H Me 122 Me H Me 7-Cl H NH2 123 Me H Me 7-Cl H OH 124 Me H Me 7-Cl Me Me 125 Me H Me 7-Cl Me NH2 126 Me H Me 7-Cl Me OH 127 Me H Me 5-NH2 H Me 128 Me H Me 5-NH2 H NH2 129 Me H Me 5-NH2 H OH 130 Me H Me 5-NH2 Me Me 131 Me H Me 5-NH2 Me NH2 132 Me H Me 5-NH2 Me OH 133 Me H Me 6-NH2 H Me 134 Me H Me 6-NH2 H NH2 135 Me H Me 6-NH2 H OH 136 Me H Me 6-NH2 Me Me 137 Me H Me 6-NH2 Me NH2 138 Me H Me 6-NH2 Me OH 139 Me H Me 7-NH2 H Me 140 Me H Me 7-NH2 H NH2 141 Me H Me 7-NH2 H OH 142 Me H Me 7-NH2 Me Me 143 Me H Me 7-NH2 Me NH2 144 Me H Me 7-NH2 Me OH 145 Me H Me 5-Me H Me 146 Me H Me 5-Me H NH2 147 Me H Me 5-Me H OH 148 Me H Me 5-Me Me Me 149 Me H Me 5-Me Me NH2 150 Me H Me 5-Me Me OH 151 Me H Me 6-Me H Me 152 Me H Me 6-Me H NH2 153 Me H Me 6-Me H OH 154 Me H Me 6-Me Me Me 155 Me H Me 6-Me Me NH2 156 Me H Me 6-Me Me OH 157 Me H Me 7-Me H Me 158 Me H Me 7-Me H NH2 159 Me H Me 7-Me H OH 160 Me H Me 7-Me Me Me

TABLE 5 Compound No. R1 R2 R3 R3′ R4 R5 161 Me H Me 7-Me Me NH2 162 Me H Me 7-Me Me OH 163 Me OH Cl 5-Cl H Me 164 Me OH Cl 5-Cl H NH2 165 Me OH Cl 5-Cl H OH 166 Me OH Cl 5-Cl Me Me 167 Me OH Cl 5-Cl Me NH2 168 Me OH Cl 5-Cl Me OH 169 Me OH Cl 6-Cl H Me 170 Me OH Cl 6-Cl H NH2 171 Me OH Cl 6-Cl H OH 172 Me OH Cl 6-Cl Me Me 173 Me OH Cl 6-Cl Me NH2 174 Me OH Cl 6-Cl Me OH 175 Me OH Cl 7-Cl H Me 176 Me OH Cl 7-Cl H NH2 177 Me OH Cl 7-Cl H OH 178 Me OH Cl 7-Cl Me Me 179 Me OH Cl 7-Cl Me NH2 180 Me OH Cl 7-Cl Me OH 181 Me OH Cl 5-NH2 H Me 182 Me OH Cl 5-NH2 H NH2 183 Me OH Cl 5-NH2 H OH 184 Me OH Cl 5-NH2 Me Me 185 Me OH Cl 5-NH2 Me NH2 186 Me OH Cl 5-NH2 Me OH 187 Me OH Cl 6-NH2 H Me 188 Me OH Cl 6-NH2 H NH2 189 Me OH Cl 6-NH2 H OH 190 Me OH Cl 6-NH2 Me Me 191 Me OH Cl 6-NH2 Me NH2 192 Me OH Cl 6-NH2 Me OH 193 Me OH Cl 7-NH2 H Me 194 Me OH Cl 7-NH2 H NH2 195 Me OH Cl 7-NH2 H OH 196 Me OH Cl 7-NH2 Me Me 197 Me OH Cl 7-NH2 Me NH2 198 Me OH Cl 7-NH2 Me OH 199 Me OH Cl 5-Me H Me 200 Me OH Cl 5-Me H NH2

TABLE 6 Compound No. R1 R2 R3 R3′ R4 R5 201 Me OH Cl 5-Me H OH 202 Me OH Cl 5-Me Me Me 203 Me OH Cl 5-Me Me NH2 204 Me OH Cl 5-Me Me OH 205 Me OH Cl 6-Me H Me 206 Me OH Cl 6-Me H NH2 207 Me OH Cl 6-Me H OH 208 Me OH Cl 6-Me Me Me 209 Me OH Cl 6-Me Me NH2 210 Me OH Cl 6-Me Me OH 211 Me OH Cl 7-Me H Me 212 Me OH Cl 7-Me H NH2 213 Me OH Cl 7-Me H OH 214 Me OH Cl 7-Me Me Me 215 Me OH Cl 7-Me Me NH2 216 Me OH Cl 7-Me Me OH 217 Me OH NH2 5-Cl H Me 218 Me OH NH2 5-Cl H NH2 219 Me OH NH2 5-Cl H OH 220 Me OH NH2 5-Cl Me Me 221 Me OH NH2 5-Cl Me NH2 222 Me OH NH2 5-Cl Me OH 223 Me OH NH2 6-Cl H Me 224 Me OH NH2 6-Cl H NH2 225 Me OH NH2 6-Cl H OH 226 Me OH NH2 6-Cl Me Me 227 Me OH NH2 6-Cl Me NH2 228 Me OH NH2 6-Cl Me OH 229 Me OH NH2 7-Cl H Me 230 Me OH NH2 7-Cl H NH2 231 Me OH NH2 7-Cl H OH 232 Me OH NH2 7-Cl Me Me 233 Me OH NH2 7-Cl Me NH2 234 Me OH NH2 7-Cl Me OH 235 Me OH NH2 5-NH2 H Me 236 Me OH NH2 5-NH2 H NH2 237 Me OH NH2 5-NH2 H OH 238 Me OH NH2 5-NH2 Me Me 239 Me OH NH2 5-NH2 Me NH2 240 Me OH NH2 5-NH2 Me OH

TABLE 7 Compound No. R1 R2 R3 R3′ R4 R5 241 Me OH NH2 6-NH2 H Me 242 Me OH NH2 6-NH2 H NH2 243 Me OH NH2 6-NH2 H OH 244 Me OH NH2 6-NH2 Me Me 245 Me OH NH2 6-NH2 Me NH2 246 Me OH NH2 6-NH2 Me OH 247 Me OH NH2 7-NH2 H Me 248 Me OH NH2 7-NH2 H NH2 249 Me OH NH2 7-NH2 H OH 250 Me OH NH2 7-NH2 Me Me 251 Me OH NH2 7-NH2 Me NH2 252 Me OH NH2 7-NH2 Me OH 253 Me OH NH2 5-Me H Me 254 Me OH NH2 5-Me H NH2 255 Me OH NH2 5-Me H OH 256 Me OH NH2 5-Me Me Me 257 Me OH NH2 5-Me Me NH2 258 Me OH NH2 5-Me Me OH 259 Me OH NH2 6-Me H Me 260 Me OH NH2 6-Me H NH2 261 Me OH NH2 6-Me H OH 262 Me OH NH2 6-Me Me Me 263 Me OH NH2 6-Me Me NH2 264 Me OH NH2 6-Me Me OH 265 Me OH NH2 7-Me H Me 266 Me OH NH2 7-Me H NH2 267 Me OH NH2 7-Me H OH 268 Me OH NH2 7-Me Me Me 269 Me OH NH2 7-Me Me NH2 270 Me OH NH2 7-Me Me OH 271 Me OH Me 5-Cl H Me 272 Me OH Me 5-Cl H NH2 273 Me OH Me 5-Cl H OH 274 Me OH Me 5-Cl Me Me 275 Me OH Me 5-Cl Me NH2 276 Me OH Me 5-Cl Me OH 277 Me OH Me 6-Cl H Me 278 Me OH Me 6-Cl H NH2 279 Me OH Me 6-Cl H OH 280 Me OH Me 6-Cl Me Me

TABLE 8 Compound No. R1 R2 R3 R3′ R4 R5 281 Me OH Me 6-Cl Me NH2 282 Me OH Me 6-Cl Me OH 283 Me OH Me 7-Cl H Me 284 Me OH Me 7-Cl H NH2 285 Me OH Me 7-Cl H OH 286 Me OH Me 7-Cl Me Me 287 Me OH Me 7-Cl Me NH2 288 Me OH Me 7-Cl Me OH 289 Me OH Me 5-NH2 H Me 290 Me OH Me 5-NH2 H NH2 291 Me OH Me 5-NH2 H OH 292 Me OH Me 5-NH2 Me Me 293 Me OH Me 5-NH2 Me NH2 294 Me OH Me 5-NH2 Me OH 295 Me OH Me 6-NH2 H Me 296 Me OH Me 6-NH2 H NH2 297 Me OH Me 6-NH2 H OH 298 Me OH Me 6-NH2 Me Me 299 Me OH Me 6-NH2 Me NH2 300 Me OH Me 6-NH2 Me OH 301 Me OH Me 7-NH2 H Me 302 Me OH Me 7-NH2 H NH2 303 Me OH Me 7-NH2 H OH 304 Me OH Me 7-NH2 Me Me 305 Me OH Me 7-NH2 Me NH2 306 Me OH Me 7-NH2 Me OH 307 Me OH Me 5-Me H Me 308 Me OH Me 5-Me H NH2 309 Me OH Me 5-Me H OH 310 Me OH Me 5-Me Me Me 311 Me OH Me 5-Me Me NH2 312 Me OH Me 5-Me Me OH 313 Me OH Me 6-Me H Me 314 Me OH Me 6-Me H NH2 315 Me OH Me 6-Me H OH 316 Me OH Me 6-Me Me Me 317 Me OH Me 6-Me Me NH2 318 Me OH Me 6-Me Me OH 319 Me OH Me 7-Me H Me 320 Me OH Me 7-Me H NH2

TABLE 9 Compound No. R1 R2 R3 R3′ R4 R5 321 Me OH Me 7-Me H OH 322 Me OH Me 7-Me Me Me 323 Me OH Me 7-Me Me NH2 324 Me OH Me 7-Me Me OH 325 Me OMe Cl 5-Cl H Me 326 Me OMe Cl 5-Cl H NH2 327 Me OMe Cl 5-Cl H OH 328 Me OMe Cl 5-Cl Me Me 329 Me OMe Cl 5-Cl Me NH2 330 Me OMe Cl 5-Cl Me OH 331 Me OMe Cl 6-Cl H Me 332 Me OMe Cl 6-Cl H NH2 333 Me OMe Cl 6-Cl H OH 334 Me OMe Cl 6-Cl Me Me 335 Me OMe Cl 6-Cl Me NH2 336 Me OMe Cl 6-Cl Me OH 337 Me OMe Cl 7-Cl H Me 338 Me OMe Cl 7-Cl H NH2 339 Me OMe Cl 7-Cl H OH 340 Me OMe Cl 7-Cl Me Me 341 Me OMe Cl 7-Cl Me NH2 342 Me OMe Cl 7-Cl Me OH 343 Me OMe Cl 5-NH2 H Me 344 Me OMe Cl 5-NH2 H NH2 345 Me OMe Cl 5-NH2 H OH 346 Me OMe Cl 5-NH2 Me Me 347 Me OMe Cl 5-NH2 Me NH2 348 Me OMe Cl 5-NH2 Me OH 349 Me OMe Cl 6-NH2 H Me 350 Me OMe Cl 6-NH2 H NH2 351 Me OMe Cl 6-NH2 H OH 352 Me OMe Cl 6-NH2 Me Me 353 Me OMe Cl 6-NH2 Me NH2 354 Me OMe Cl 6-NH2 Me OH 355 Me OMe Cl 7-NH2 H Me 356 Me OMe Cl 7-NH2 H NH2 357 Me OMe Cl 7-NH2 H OH 358 Me OMe Cl 7-NH2 Me Me 359 Me OMe Cl 7-NH2 Me NH2 360 Me OMe Cl 7-NH2 Me OH

TABLE 10 Compound No. R1 R2 R3 R3′ R4 R5 361 Me OMe Cl 5-Me H Me 362 Me OMe Cl 5-Me H NH2 363 Me OMe Cl 5-Me H OH 364 Me OMe Cl 5-Me Me Me 365 Me OMe Cl 5-Me Me NH2 366 Me OMe Cl 5-Me Me OH 367 Me OMe Cl 6-Me H Me 368 Me OMe Cl 6-Me H NH2 369 Me OMe Cl 6-Me H OH 370 Me OMe Cl 6-Me Me Me 371 Me OMe Cl 6-Me Me NH2 372 Me OMe Cl 6-Me Me OH 373 Me OMe Cl 7-Me H Me 374 Me OMe Cl 7-Me H NH2 375 Me OMe Cl 7-Me H OH 376 Me OMe Cl 7-Me Me Me 377 Me OMe Cl 7-Me Me NH2 378 Me OMe Cl 7-Me Me OH 379 Me OMe NH2 5-Cl H Me 380 Me OMe NH2 5-Cl H NH2 381 Me OMe NH2 5-Cl H OH 382 Me OMe NH2 5-Cl Me Me 383 Me OMe NH2 5-Cl Me NH2 384 Me OMe NH2 5-Cl Me OH 385 Me OMe NH2 6-Cl H Me 386 Me OMe NH2 6-Cl H NH2 387 Me OMe NH2 6-Cl H OH 388 Me OMe NH2 6-Cl Me Me 389 Me OMe NH2 6-Cl Me NH2 390 Me OMe NH2 6-Cl Me OH 391 Me OMe NH2 7-Cl H Me 392 Me OMe NH2 7-Cl H NH2 393 Me OMe NH2 7-Cl H OH 394 Me OMe NH2 7-Cl Me Me 395 Me OMe NH2 7-Cl Me NH2 396 Me OMe NH2 7-Cl Me OH 397 Me OMe NH2 5-NH2 H Me 398 Me OMe NH2 5-NH2 H NH2 399 Me OMe NH2 5-NH2 H OH 400 Me OMe NH2 5-NH2 Me Me

TABLE 11 Compound No. R1 R2 R3 R3′ R4 R5 401 Me OMe NH2 5-NH2 Me NH2 402 Me OMe NH2 5-NH2 Me OH 403 Me OMe NH2 6-NH2 H Me 404 Me OMe NH2 6-NH2 H NH2 405 Me OMe NH2 6-NH2 H OH 406 Me OMe NH2 6-NH2 Me Me 407 Me OMe NH2 6-NH2 Me NH2 408 Me OMe NH2 6-NH2 Me OH 409 Me OMe NH2 7-NH2 H Me 410 Me OMe NH2 7-NH2 H NH2 411 Me OMe NH2 7-NH2 H OH 412 Me OMe NH2 7-NH2 Me Me 413 Me OMe NH2 7-NH2 Me NH2 414 Me OMe NH2 7-NH2 Me OH 415 Me OMe NH2 5-Me H Me 416 Me OMe NH2 5-Me H NH2 417 Me OMe NH2 5-Me H OH 418 Me OMe NH2 5-Me Me Me 419 Me OMe NH2 5-Me Me NH2 420 Me OMe NH2 5-Me Me OH 421 Me OMe NH2 6-Me H Me 422 Me OMe NH2 6-Me H NH2 423 Me OMe NH2 6-Me H OH 424 Me OMe NH2 6-Me Me Me 425 Me OMe NH2 6-Me Me NH2 426 Me OMe NH2 6-Me Me OH 427 Me OMe NH2 7-Me H Me 428 Me OMe NH2 7-Me H NH2 429 Me OMe NH2 7-Me H OH 430 Me OMe NH2 7-Me Me Me 431 Me OMe NH2 7-Me Me NH2 432 Me OMe NH2 7-Me Me OH 433 Me OMe Me 5-Cl H Me 434 Me OMe Me 5-Cl H NH2 435 Me OMe Me 5-Cl H OH 436 Me OMe Me 5-Cl Me Me 437 Me OMe Me 5-Cl Me NH2 438 Me OMe Me 5-Cl Me OH 439 Me OMe Me 6-Cl H Me 440 Me OMe Me 6-Cl H NH2

TABLE 12 Compound No. R1 R2 R3 R3′ R4 R5 441 Me OMe Me 6-Cl H OH 442 Me OMe Me 6-Cl Me Me 443 Me OMe Me 6-Cl Me NH2 444 Me OMe Me 6-Cl Me OH 445 Me OMe Me 7-Cl H Me 446 Me OMe Me 7-Cl H NH2 447 Me OMe Me 7-Cl H OH 448 Me OMe Me 7-Cl Me Me 449 Me OMe Me 7-Cl Me NH2 450 Me OMe Me 7-Cl Me OH 451 Me OMe Me 5-NH2 H Me 452 Me OMe Me 5-NH2 H NH2 453 Me OMe Me 5-NH2 H OH 454 Me OMe Me 5-NH2 Me Me 455 Me OMe Me 5-NH2 Me NH2 456 Me OMe Me 5-NH2 Me OH 457 Me OMe Me 6-NH2 H Me 458 Me OMe Me 6-NH2 H NH2 459 Me OMe Me 6-NH2 H OH 460 Me OMe Me 6-NH2 Me Me 461 Me OMe Me 6-NH2 Me NH2 462 Me OMe Me 6-NH2 Me OH 463 Me OMe Me 7-NH2 H Me 464 Me OMe Me 7-NH2 H NH2 465 Me OMe Me 7-NH2 H OH 466 Me OMe Me 7-NH2 Me Me 467 Me OMe Me 7-NH2 Me NH2 468 Me OMe Me 7-NH2 Me OH 469 Me OMe Me 5-Me H Me 470 Me OMe Me 5-Me H NH2 471 Me OMe Me 5-Me H OH 472 Me OMe Me 5-Me Me Me 473 Me OMe Me 5-Me Me NH2 474 Me OMe Me 5-Me Me OH 475 Me OMe Me 6-Me H Me 476 Me OMe Me 6-Me H NH2 477 Me OMe Me 6-Me H OH 478 Me OMe Me 6-Me Me Me 479 Me OMe Me 6-Me Me NH2 480 Me OMe Me 6-Me Me OH

TABLE 13 Compound No. R1 R2 R3 R3′ R4 R5 481 Me OMe Me 7-Me H Me 482 Me OMe Me 7-Me H NH2 483 Me OMe Me 7-Me H OH 484 Me OMe Me 7-Me Me Me 485 Me OMe Me 7-Me Me NH2 486 Me OMe Me 7-Me Me OH 487 CH2CH2Ph H Cl 5-Cl H Me 488 CH2CH2Ph H Cl 5-Cl H NH2 489 CH2CH2Ph H Cl 5-Cl H OH 490 CH2CH2Ph H Cl 5-Cl Me Me 491 CH2CH2Ph H Cl 5-Cl Me NH2 492 CH2CH2Ph H Cl 5-Cl Me OH 493 CH2CH2Ph H Cl 6-Cl H Me 494 CH2CH2Ph H Cl 6-Cl H NH2 495 CH2CH2Ph H Cl 6-Cl H OH 496 CH2CH2Ph H Cl 6-Cl Me Me 497 CH2CH2Ph H Cl 6-Cl Me NH2 498 CH2CH2Ph H Cl 6-Cl Me OH 499 CH2CH2Ph H Cl 7-Cl H Me 500 CH2CH2Ph H Cl 7-Cl H NH2 501 CH2CH2Ph H Cl 7-Cl H OH 502 CH2CH2Ph H Cl 7-Cl Me Me 503 CH2CH2Ph H Cl 7-Cl Me NH2 504 CH2CH2Ph H Cl 7-Cl Me OH 505 CH2CH2Ph H Cl 5-NH2 H Me 506 CH2CH2Ph H Cl 5-NH2 H NH2 507 CH2CH2Ph H Cl 5-NH2 H OH 508 CH2CH2Ph H Cl 5-NH2 Me Me 509 CH2CH2Ph H Cl 5-NH2 Me NH2 510 CH2CH2Ph H Cl 5-NH2 Me OH 511 CH2CH2Ph H Cl 6-NH2 H Me 512 CH2CH2Ph H Cl 6-NH2 H NH2 513 CH2CH2Ph H Cl 6-NH2 H OH 514 CH2CH2Ph H Cl 6-NH2 Me Me 515 CH2CH2Ph H Cl 6-NH2 Me NH2 516 CH2CH2Ph H Cl 6-NH2 Me OH 517 CH2CH2Ph H Cl 7-NH2 H Me 518 CH2CH2Ph H Cl 7-NH2 H NH2 519 CH2CH2Ph H Cl 7-NH2 H OH 520 CH2CH2Ph H Cl 7-NH2 Me Me

TABLE 14 Compound No. R1 R2 R3 R3′ R4 R5 521 CH2CH2Ph H Cl 7-NH2 Me NH2 522 CH2CH2Ph H Cl 7-NH2 Me OH 523 CH2CH2Ph H Cl 5-Me H Me 524 CH2CH2Ph H Cl 5-Me H NH2 525 CH2CH2Ph H Cl 5-Me H OH 526 CH2CH2Ph H Cl 5-Me Me Me 527 CH2CH2Ph H Cl 5-Me Me NH2 528 CH2CH2Ph H Cl 5-Me Me OH 529 CH2CH2Ph H Cl 6-Me H Me 530 CH2CH2Ph H Cl 6-Me H NH2 531 CH2CH2Ph H Cl 6-Me H OH 532 CH2CH2Ph H Cl 6-Me Me Me 533 CH2CH2Ph H Cl 6-Me Me NH2 534 CH2CH2Ph H Cl 6-Me Me OH 535 CH2CH2Ph H Cl 7-Me H Me 536 CH2CH2Ph H Cl 7-Me H NH2 537 CH2CH2Ph H Cl 7-Me H OH 538 CH2CH2Ph H Cl 7-Me Me Me 539 CH2CH2Ph H Cl 7-Me Me NH2 540 CH2CH2Ph H Cl 7-Me Me OH 541 CH2CH2Ph H NH2 5-Cl H Me 542 CH2CH2Ph H NH2 5-Cl H NH2 543 CH2CH2Ph H NH2 5-Cl H OH 544 CH2CH2Ph H NH2 5-Cl Me Me 545 CH2CH2Ph H NH2 5-Cl Me NH2 546 CH2CH2Ph H NH2 5-Cl Me OH 547 CH2CH2Ph H NH2 6-Cl H Me 548 CH2CH2Ph H NH2 6-Cl H NH2 549 CH2CH2Ph H NH2 6-Cl H OH 550 CH2CH2Ph H NH2 6-Cl Me Me 551 CH2CH2Ph H NH2 6-Cl Me NH2 552 CH2CH2Ph H NH2 6-Cl Me OH 553 CH2CH2Ph H NH2 7-Cl H Me 554 CH2CH2Ph H NH2 7-Cl H NH2 555 CH2CH2Ph H NH2 7-Cl H OH 556 CH2CH2Ph H NH2 7-Cl Me Me 557 CH2CH2Ph H NH2 7-Cl Me NH2 558 CH2CH2Ph H NH2 7-Cl Me OH 559 CH2CH2Ph H NH2 5-NH2 H Me 560 CH2CH2Ph H NH2 5-NH2 H NH2

TABLE 15 Compound No. R1 R2 R3 R3′ R4 R5 561 CH2CH2Ph H NH2 5-NH2 H OH 562 CH2CH2Ph H NH2 5-NH2 Me Me 563 CH2CH2Ph H NH2 5-NH2 Me NH2 564 CH2CH2Ph H NH2 5-NH2 Me OH 565 CH2CH2Ph H NH2 6-NH2 H Me 566 CH2CH2Ph H NH2 6-NH2 H NH2 567 CH2CH2Ph H NH2 6-NH2 H OH 568 CH2CH2Ph H NH2 6-NH2 Me Me 569 CH2CH2Ph H NH2 6-NH2 Me NH2 570 CH2CH2Ph H NH2 6-NH2 Me OH 571 CH2CH2Ph H NH2 7-NH2 H Me 572 CH2CH2Ph H NH2 7-NH2 H NH2 573 CH2CH2Ph H NH2 7-NH2 H OH 574 CH2CH2Ph H NH2 7-NH2 Me Me 575 CH2CH2Ph H NH2 7-NH2 Me NH2 576 CH2CH2Ph H NH2 7-NH2 Me OH 577 CH2CH2Ph H NH2 5-Me H Me 578 CH2CH2Ph H NH2 5-Me H NH2 579 CH2CH2Ph H NH2 5-Me H OH 580 CH2CH2Ph H NH2 5-Me Me Me 581 CH2CH2Ph H NH2 5-Me Me NH2 582 CH2CH2Ph H NH2 5-Me Me OH 583 CH2CH2Ph H NH2 6-Me H Me 584 CH2CH2Ph H NH2 6-Me H NH2 585 CH2CH2Ph H NH2 6-Me H OH 586 CH2CH2Ph H NH2 6-Me Me Me 587 CH2CH2Ph H NH2 6-Me Me NH2 588 CH2CH2Ph H NH2 6-Me Me OH 589 CH2CH2Ph H NH2 7-Me H Me 590 CH2CH2Ph H NH2 7-Me H NH2 591 CH2CH2Ph H NH2 7-Me H OH 592 CH2CH2Ph H NH2 7-Me Me Me 593 CH2CH2Ph H NH2 7-Me Me NH2 594 CH2CH2Ph H NH2 7-Me Me OH 595 CH2CH2Ph H Me 5-Cl H Me 596 CH2CH2Ph H Me 5-Cl H NH2 597 CH2CH2Ph H Me 5-Cl H OH 598 CH2CH2Ph H Me 5-Cl Me Me 599 CH2CH2Ph H Me 5-Cl Me NH2 600 CH2CH2Ph H Me 5-Cl Me OH

TABLE 16 Compound No. R1 R2 R3 R3′ R4 R5 601 CH2CH2Ph H Me 6-Cl H Me 602 CH2CH2Ph H Me 6-Cl H NH2 603 CH2CH2Ph H Me 6-Cl H OH 604 CH2CH2Ph H Me 6-Cl Me Me 605 CH2CH2Ph H Me 6-Cl Me NH2 606 CH2CH2Ph H Me 6-Cl Me OH 607 CH2CH2Ph H Me 7-Cl H Me 608 CH2CH2Ph H Me 7-Cl H NH2 609 CH2CH2Ph H Me 7-Cl H OH 610 CH2CH2Ph H Me 7-Cl Me Me 611 CH2CH2Ph H Me 7-Cl Me NH2 612 CH2CH2Ph H Me 7-Cl Me OH 613 CH2CH2Ph H Me 5-NH2 H Me 614 CH2CH2Ph H Me 5-NH2 H NH2 615 CH2CH2Ph H Me 5-NH2 H OH 616 CH2CH2Ph H Me 5-NH2 Me Me 617 CH2CH2Ph H Me 5-NH2 Me NH2 618 CH2CH2Ph H Me 5-NH2 Me OH 619 CH2CH2Ph H Me 6-NH2 H Me 620 CH2CH2Ph H Me 6-NH2 H NH2 621 CH2CH2Ph H Me 6-NH2 H OH 622 CH2CH2Ph H Me 6-NH2 Me Me 623 CH2CH2Ph H Me 6-NH2 Me NH2 624 CH2CH2Ph H Me 6-NH2 Me OH 625 CH2CH2Ph H Me 7-NH2 H Me 626 CH2CH2Ph H Me 7-NH2 H NH2 627 CH2CH2Ph H Me 7-NH2 H OH 628 CH2CH2Ph H Me 7-NH2 Me Me 629 CH2CH2Ph H Me 7-NH2 Me NH2 630 CH2CH2Ph H Me 7-NH2 Me OH 631 CH2CH2Ph H Me 5-Me H Me 632 CH2CH2Ph H Me 5-Me H NH2 633 CH2CH2Ph H Me 5-Me H OH 634 CH2CH2Ph H Me 5-Me Me Me 635 CH2CH2Ph H Me 5-Me Me NH2 636 CH2CH2Ph H Me 5-Me Me OH 637 CH2CH2Ph H Me 6-Me H Me 638 CH2CH2Ph H Me 6-Me H NH2 639 CH2CH2Ph H Me 6-Me H OH 640 CH2CH2Ph H Me 6-Me Me Me

TABLE 17 Compound No. R1 R2 R3 R3′ R4 R5 641 CH2CH2Ph H Me 6-Me Me NH2 642 CH2CH2Ph H Me 6-Me Me OH 643 CH2CH2Ph H Me 7-Me H Me 644 CH2CH2Ph H Me 7-Me H NH2 645 CH2CH2Ph H Me 7-Me H OH 646 CH2CH2Ph H Me 7-Me Me Me 647 CH2CH2Ph H Me 7-Me Me NH2 648 CH2CH2Ph H Me 7-Me Me OH 649 CH2CH2Ph OH Cl 5-Cl H Me 650 CH2CH2Ph OH Cl 5-Cl H NH2 651 CH2CH2Ph OH Cl 5-Cl H OH 652 CH2CH2Ph OH Cl 5-Cl Me Me 653 CH2CH2Ph OH Cl 5-Cl Me NH2 654 CH2CH2Ph OH Cl 5-Cl Me OH 655 CH2CH2Ph OH Cl 6-Cl H Me 656 CH2CH2Ph OH Cl 6-Cl H NH2 657 CH2CH2Ph OH Cl 6-Cl H OH 658 CH2CH2Ph OH Cl 6-Cl Me Me 659 CH2CH2Ph OH Cl 6-Cl Me NH2 660 CH2CH2Ph OH Cl 6-Cl Me OH 661 CH2CH2Ph OH Cl 7-Cl H Me 662 CH2CH2Ph OH Cl 7-Cl H NH2 663 CH2CH2Ph OH Cl 7-Cl H OH 664 CH2CH2Ph OH Cl 7-Cl Me Me 665 CH2CH2Ph OH Cl 7-Cl Me NH2 666 CH2CH2Ph OH Cl 7-Cl Me OH 667 CH2CH2Ph OH Cl 5-NH2 H Me 668 CH2CH2Ph OH Cl 5-NH2 H NH2 669 CH2CH2Ph OH Cl 5-NH2 H OH 670 CH2CH2Ph OH Cl 5-NH2 Me Me 671 CH2CH2Ph OH Cl 5-NH2 Me NH2 672 CH2CH2Ph OH Cl 5-NH2 Me OH 673 CH2CH2Ph OH Cl 6-NH2 H Me 674 CH2CH2Ph OH Cl 6-NH2 H NH2 675 CH2CH2Ph OH Cl 6-NH2 H OH 676 CH2CH2Ph OH Cl 6-NH2 Me Me 677 CH2CH2Ph OH Cl 6-NH2 Me NH2 678 CH2CH2Ph OH Cl 6-NH2 Me OH 679 CH2CH2Ph OH Cl 7-NH2 H Me 680 CH2CH2Ph OH Cl 7-NH2 H NH2

TABLE 18 Compound No. R1 R2 R3 R3′ R4 R5 681 CH2CH2Ph OH Cl 7-NH2 H OH 682 CH2CH2Ph OH Cl 7-NH2 Me Me 683 CH2CH2Ph OH Cl 7-NH2 Me NH2 684 CH2CH2Ph OH Cl 7-NH2 Me OH 685 CH2CH2Ph OH Cl 5-Me H Me 686 CH2CH2Ph OH Cl 5-Me H NH2 687 CH2CH2Ph OH Cl 5-Me H OH 688 CH2CH2Ph OH Cl 5-Me Me Me 689 CH2CH2Ph OH Cl 5-Me Me NH2 690 CH2CH2Ph OH Cl 5-Me Me OH 691 CH2CH2Ph OH Cl 6-Me H Me 692 CH2CH2Ph OH Cl 6-Me H NH2 693 CH2CH2Ph OH Cl 6-Me H OH 694 CH2CH2Ph OH Cl 6-Me Me Me 695 CH2CH2Ph OH Cl 6-Me Me NH2 696 CH2CH2Ph OH Cl 6-Me Me OH 697 CH2CH2Ph OH Cl 7-Me H Me 698 CH2CH2Ph OH Cl 7-Me H NH2 699 CH2CH2Ph OH Cl 7-Me H OH 700 CH2CH2Ph OH Cl 7-Me Me Me 701 CH2CH2Ph OH Cl 7-Me Me NH2 702 CH2CH2Ph OH Cl 7-Me Me OH 703 CH2CH2Ph OH NH2 5-Cl H Me 704 CH2CH2Ph OH NH2 5-Cl H NH2 705 CH2CH2Ph OH NH2 5-Cl H OH 706 CH2CH2Ph OH NH2 5-Cl Me Me 707 CH2CH2Ph OH NH2 5-Cl Me NH2 708 CH2CH2Ph OH NH2 5-Cl Me OH 709 CH2CH2Ph OH NH2 6-Cl H Me 710 CH2CH2Ph OH NH2 6-Cl H NH2 711 CH2CH2Ph OH NH2 6-Cl H OH 712 CH2CH2Ph OH NH2 6-Cl Me Me 713 CH2CH2Ph OH NH2 6-Cl Me NH2 714 CH2CH2Ph OH NH2 6-Cl Me OH 715 CH2CH2Ph OH NH2 7-Cl H Me 716 CH2CH2Ph OH NH2 7-Cl H NH2 717 CH2CH2Ph OH NH2 7-Cl H OH 718 CH2CH2Ph OH NH2 7-Cl Me Me 719 CH2CH2Ph OH NH2 7-Cl Me NH2 720 CH2CH2Ph OH NH2 7-Cl Me OH

TABLE 19 Compound No. R1 R2 R3 R3′ R4 R5 721 CH2CH2Ph OH NH2 5-NH2 H Me 722 CH2CH2Ph OH NH2 5-NH2 H NH2 723 CH2CH2Ph OH NH2 5-NH2 H OH 724 CH2CH2Ph OH NH2 5-NH2 Me Me 725 CH2CH2Ph OH NH2 5-NH2 Me NH2 726 CH2CH2Ph OH NH2 5-NH2 Me OH 727 CH2CH2Ph OH NH2 6-NH2 H Me 728 CH2CH2Ph OH NH2 6-NH2 H NH2 729 CH2CH2Ph OH NH2 6-NH2 H OH 730 CH2CH2Ph OH NH2 6-NH2 Me Me 731 CH2CH2Ph OH NH2 6-NH2 Me NH2 732 CH2CH2Ph OH NH2 6-NH2 Me OH 733 CH2CH2Ph OH NH2 7-NH2 H Me 734 CH2CH2Ph OH NH2 7-NH2 H NH2 735 CH2CH2Ph OH NH2 7-NH2 H OH 736 CH2CH2Ph OH NH2 7-NH2 Me Me 737 CH2CH2Ph OH NH2 7-NH2 Me NH2 738 CH2CH2Ph OH NH2 7-NH2 Me OH 739 CH2CH2Ph OH NH2 5-Me H Me 740 CH2CH2Ph OH NH2 5-Me H NH2 741 CH2CH2Ph OH NH2 5-Me H OH 742 CH2CH2Ph OH NH2 5-Me Me Me 743 CH2CH2Ph OH NH2 5-Me Me NH2 744 CH2CH2Ph OH NH2 5-Me Me OH 745 CH2CH2Ph OH NH2 6-Me H Me 746 CH2CH2Ph OH NH2 6-Me H NH2 747 CH2CH2Ph OH NH2 6-Me H OH 748 CH2CH2Ph OH NH2 6-Me Me Me 749 CH2CH2Ph OH NH2 6-Me Me NH2 750 CH2CH2Ph OH NH2 6-Me Me OH 751 CH2CH2Ph OH NH2 7-Me H Me 752 CH2CH2Ph OH NH2 7-Me H NH2 753 CH2CH2Ph OH NH2 7-Me H OH 754 CH2CH2Ph OH NH2 7-Me Me Me 755 CH2CH2Ph OH NH2 7-Me Me NH2 756 CH2CH2Ph OH NH2 7-Me Me OH 757 CH2CH2Ph OH Me 5-Cl H Me 758 CH2CH2Ph OH Me 5-Cl H NH2 759 CH2CH2Ph OH Me 5-Cl H OH 760 CH2CH2Ph OH Me 5-Cl Me Me

TABLE 20 Compound No. R1 R2 R3 R3′ R4 R5 761 CH2CH2Ph OH Me 5-Cl Me NH2 762 CH2CH2Ph OH Me 5-Cl Me OH 763 CH2CH2Ph OH Me 6-Cl H Me 764 CH2CH2Ph OH Me 6-Cl H NH2 765 CH2CH2Ph OH Me 6-Cl H OH 766 CH2CH2Ph OH Me 6-Cl Me Me 767 CH2CH2Ph OH Me 6-Cl Me NH2 768 CH2CH2Ph OH Me 6-Cl Me OH 769 CH2CH2Ph OH Me 7-Cl H Me 770 CH2CH2Ph OH Me 7-Cl H NH2 771 CH2CH2Ph OH Me 7-Cl H OH 772 CH2CH2Ph OH Me 7-Cl Me Me 773 CH2CH2Ph OH Me 7-Cl Me NH2 774 CH2CH2Ph OH Me 7-Cl Me OH 775 CH2CH2Ph OH Me 5-NH2 H Me 776 CH2CH2Ph OH Me 5-NH2 H NH2 777 CH2CH2Ph OH Me 5-NH2 H OH 778 CH2CH2Ph OH Me 5-NH2 Me Me 779 CH2CH2Ph OH Me 5-NH2 Me NH2 780 CH2CH2Ph OH Me 5-NH2 Me OH 781 CH2CH2Ph OH Me 6-NH2 H Me 782 CH2CH2Ph OH Me 6-NH2 H NH2 783 CH2CH2Ph OH Me 6-NH2 H OH 784 CH2CH2Ph OH Me 6-NH2 Me Me 785 CH2CH2Ph OH Me 6-NH2 Me NH2 786 CH2CH2Ph OH Me 6-NH2 Me OH 787 CH2CH2Ph OH Me 7-NH2 H Me 788 CH2CH2Ph OH Me 7-NH2 H NH2 789 CH2CH2Ph OH Me 7-NH2 H OH 790 CH2CH2Ph OH Me 7-NH2 Me Me 791 CH2CH2Ph OH Me 7-NH2 Me NH2 792 CH2CH2Ph OH Me 7-NH2 Me OH 793 CH2CH2Ph OH Me 5-Me H Me 794 CH2CH2Ph OH Me 5-Me H NH2 795 CH2CH2Ph OH Me 5-Me H OH 796 CH2CH2Ph OH Me 5-Me Me Me 797 CH2CH2Ph OH Me 5-Me Me NH2 798 CH2CH2Ph OH Me 5-Me Me OH 799 CH2CH2Ph OH Me 6-Me H Me 800 CH2CH2Ph OH Me 6-Me H NH2

TABLE 21 Compound No. R1 R2 R3 R3′ R4 R5 801 CH2CH2Ph OH Me 6-Me H OH 802 CH2CH2Ph OH Me 6-Me Me Me 803 CH2CH2Ph OH Me 6-Me Me NH2 804 CH2CH2Ph OH Me 6-Me Me OH 805 CH2CH2Ph OH Me 7-Me H Me 806 CH2CH2Ph OH Me 7-Me H NH2 807 CH2CH2Ph OH Me 7-Me H OH 808 CH2CH2Ph OH Me 7-Me Me Me 809 CH2CH2Ph OH Me 7-Me Me NH2 810 CH2CH2Ph OH Me 7-Me Me OH 811 CH2CH2Ph OMe Cl 5-Cl H Me 812 CH2CH2Ph OMe Cl 5-Cl H NH2 813 CH2CH2Ph OMe Cl 5-Cl H OH 814 CH2CH2Ph OMe Cl 5-Cl Me Me 815 CH2CH2Ph OMe Cl 5-Cl Me NH2 816 CH2CH2Ph OMe Cl 5-Cl Me OH 817 CH2CH2Ph OMe Cl 6-Cl H Me 818 CH2CH2Ph OMe Cl 6-Cl H NH2 819 CH2CH2Ph OMe Cl 6-Cl H OH 820 CH2CH2Ph OMe Cl 6-Cl Me Me 821 CH2CH2Ph OMe Cl 6-Cl Me NH2 822 CH2CH2Ph OMe Cl 6-Cl Me OH 823 CH2CH2Ph OMe Cl 7-Cl H Me 824 CH2CH2Ph OMe Cl 7-Cl H NH2 825 CH2CH2Ph OMe Cl 7-Cl H OH 826 CH2CH2Ph OMe Cl 7-Cl Me Me 827 CH2CH2Ph OMe Cl 7-Cl Me NH2 828 CH2CH2Ph OMe Cl 7-Cl Me OH 829 CH2CH2Ph OMe Cl 5-NH2 H Me 830 CH2CH2Ph OMe Cl 5-NH2 H NH2 831 CH2CH2Ph OMe Cl 5-NH2 H OH 832 CH2CH2Ph OMe Cl 5-NH2 Me Me 833 CH2CH2Ph OMe Cl 5-NH2 Me NH2 834 CH2CH2Ph OMe Cl 5-NH2 Me OH 835 CH2CH2Ph OMe Cl 6-NH2 H Me 836 CH2CH2Ph OMe Cl 6-NH2 H NH2 837 CH2CH2Ph OMe Cl 6-NH2 H OH 838 CH2CH2Ph OMe Cl 6-NH2 Me Me 839 CH2CH2Ph OMe Cl 6-NH2 Me NH2 840 CH2CH2Ph OMe Cl 6-NH2 Me OH

TABLE 22 Compound No. R1 R2 R3 R3′ R4 R5 841 CH2CH2Ph OMe Cl 7-NH2 H Me 842 CH2CH2Ph OMe Cl 7-NH2 H NH2 843 CH2CH2Ph OMe Cl 7-NH2 H OH 844 CH2CH2Ph OMe Cl 7-NH2 Me Me 845 CH2CH2Ph OMe Cl 7-NH2 Me NH2 846 CH2CH2Ph OMe Cl 7-NH2 Me OH 847 CH2CH2Ph OMe Cl 5-Me H Me 848 CH2CH2Ph OMe Cl 5-Me H NH2 849 CH2CH2Ph OMe Cl 5-Me H OH 850 CH2CH2Ph OMe Cl 5-Me Me Me 851 CH2CH2Ph OMe Cl 5-Me Me NH2 852 CH2CH2Ph OMe Cl 5-Me Me OH 853 CH2CH2Ph OMe Cl 6-Me H Me 854 CH2CH2Ph OMe Cl 6-Me H NH2 855 CH2CH2Ph OMe Cl 6-Me H OH 856 CH2CH2Ph OMe Cl 6-Me Me Me 857 CH2CH2Ph OMe Cl 6-Me Me NH2 858 CH2CH2Ph OMe Cl 6-Me Me OH 859 CH2CH2Ph OMe Cl 7-Me H Me 860 CH2CH2Ph OMe Cl 7-Me H NH2 861 CH2CH2Ph OMe Cl 7-Me H OH 862 CH2CH2Ph OMe Cl 7-Me Me Me 863 CH2CH2Ph OMe Cl 7-Me Me NH2 864 CH2CH2Ph OMe Cl 7-Me Me OH 865 CH2CH2Ph OMe NH2 5-Cl H Me 866 CH2CH2Ph OMe NH2 5-Cl H NH2 867 CH2CH2Ph OMe NH2 5-Cl H OH 868 CH2CH2Ph OMe NH2 5-Cl Me Me 869 CH2CH2Ph OMe NH2 5-Cl Me NH2 870 CH2CH2Ph OMe NH2 5-Cl Me OH 871 CH2CH2Ph OMe NH2 6-Cl H Me 872 CH2CH2Ph OMe NH2 6-Cl H NH2 873 CH2CH2Ph OMe NH2 6-Cl H OH 874 CH2CH2Ph OMe NH2 6-Cl Me Me 875 CH2CH2Ph OMe NH2 6-Cl Me NH2 876 CH2CH2Ph OMe NH2 6-Cl Me OH 877 CH2CH2Ph OMe NH2 7-Cl H Me 878 CH2CH2Ph OMe NH2 7-Cl H NH2 879 CH2CH2Ph OMe NH2 7-Cl H OH 880 CH2CH2Ph OMe NH2 7-Cl Me Me

TABLE 23 Compound No. R1 R2 R3 R3′ R4 R5 881 CH2CH2Ph OMe NH2 7-Cl Me NH2 882 CH2CH2Ph OMe NH2 7-Cl Me OH 883 CH2CH2Ph OMe NH2 5-NH2 H Me 884 CH2CH2Ph OMe NH2 5-NH2 H NH2 885 CH2CH2Ph OMe NH2 5-NH2 H OH 886 CH2CH2Ph OMe NH2 5-NH2 Me Me 887 CH2CH2Ph OMe NH2 5-NH2 Me NH2 888 CH2CH2Ph OMe NH2 5-NH2 Me OH 889 CH2CH2Ph OMe NH2 6-NH2 H Me 890 CH2CH2Ph OMe NH2 6-NH2 H NH2 891 CH2CH2Ph OMe NH2 6-NH2 H OH 892 CH2CH2Ph OMe NH2 6-NH2 Me Me 893 CH2CH2Ph OMe NH2 6-NH2 Me NH2 894 CH2CH2Ph OMe NH2 6-NH2 Me OH 895 CH2CH2Ph OMe NH2 7-NH2 H Me 896 CH2CH2Ph OMe NH2 7-NH2 H NH2 897 CH2CH2Ph OMe NH2 7-NH2 H OH 898 CH2CH2Ph OMe NH2 7-NH2 Me Me 899 CH2CH2Ph OMe NH2 7-NH2 Me NH2 900 CH2CH2Ph OMe NH2 7-NH2 Me OH 901 CH2CH2Ph OMe NH2 5-Me H Me 902 CH2CH2Ph OMe NH2 5-Me H NH2 903 CH2CH2Ph OMe NH2 5-Me H OH 904 CH2CH2Ph OMe NH2 5-Me Me Me 905 CH2CH2Ph OMe NH2 5-Me Me NH2 906 CH2CH2Ph OMe NH2 5-Me Me OH 907 CH2CH2Ph OMe NH2 6-Me H Me 908 CH2CH2Ph OMe NH2 6-Me H NH2 909 CH2CH2Ph OMe NH2 6-Me H OH 910 CH2CH2Ph OMe NH2 6-Me Me Me 911 CH2CH2Ph OMe NH2 6-Me Me NH2 912 CH2CH2Ph OMe NH2 6-Me Me OH 913 CH2CH2Ph OMe NH2 7-Me H Me 914 CH2CH2Ph OMe NH2 7-Me H NH2 915 CH2CH2Ph OMe NH2 7-Me H OH 916 CH2CH2Ph OMe NH2 7-Me Me Me 917 CH2CH2Ph OMe NH2 7-Me Me NH2 918 CH2CH2Ph OMe NH2 7-Me Me OH 919 CH2CH2Ph OMe Me 5-Cl H Me 920 CH2CH2Ph OMe Me 5-Cl H NH2

TABLE 24 Compound No. R1 R2 R3 R3′ R4 R5 921 CH2CH2Ph OMe Me 5-Cl H OH 922 CH2CH2Ph OMe Me 5-Cl Me Me 923 CH2CH2Ph OMe Me 5-Cl Me NH2 924 CH2CH2Ph OMe Me 5-Cl Me OH 925 CH2CH2Ph OMe Me 6-Cl H Me 926 CH2CH2Ph OMe Me 6-Cl H NH2 927 CH2CH2Ph OMe Me 6-Cl H OH 928 CH2CH2Ph OMe Me 6-Cl Me Me 929 CH2CH2Ph OMe Me 6-Cl Me NH2 930 CH2CH2Ph OMe Me 6-Cl Me OH 931 CH2CH2Ph OMe Me 7-Cl H Me 932 CH2CH2Ph OMe Me 7-Cl H NH2 933 CH2CH2Ph OMe Me 7-Cl H OH 934 CH2CH2Ph OMe Me 7-Cl Me Me 935 CH2CH2Ph OMe Me 7-Cl Me NH2 936 CH2CH2Ph OMe Me 7-Cl Me OH 937 CH2CH2Ph OMe Me 5-NH2 H Me 938 CH2CH2Ph OMe Me 5-NH2 H NH2 939 CH2CH2Ph OMe Me 5-NH2 H OH 940 CH2CH2Ph OMe Me 5-NH2 Me Me 941 CH2CH2Ph OMe Me 5-NH2 Me NH2 942 CH2CH2Ph OMe Me 5-NH2 Me OH 943 CH2CH2Ph OMe Me 6-NH2 H Me 944 CH2CH2Ph OMe Me 6-NH2 H NH2 945 CH2CH2Ph OMe Me 6-NH2 H OH 946 CH2CH2Ph OMe Me 6-NH2 Me Me 947 CH2CH2Ph OMe Me 6-NH2 Me NH2 948 CH2CH2Ph OMe Me 6-NH2 Me OH 949 CH2CH2Ph OMe Me 7-NH2 H Me 950 CH2CH2Ph OMe Me 7-NH2 H NH2 951 CH2CH2Ph OMe Me 7-NH2 H OH 952 CH2CH2Ph OMe Me 7-NH2 Me Me 953 CH2CH2Ph OMe Me 7-NH2 Me NH2 954 CH2CH2Ph OMe Me 7-NH2 Me OH 955 CH2CH2Ph OMe Me 5-Me H Me 956 CH2CH2Ph OMe Me 5-Me H NH2 957 CH2CH2Ph OMe Me 5-Me H OH 958 CH2CH2Ph OMe Me 5-Me Me Me 959 CH2CH2Ph OMe Me 5-Me Me NH2 960 CH2CH2Ph OMe Me 5-Me Me OH

TABLE 25 Compound No. R1 R2 R3 R3′ R4 R5 961 CH2CH2Ph OMe Me 6-Me H Me 962 CH2CH2Ph OMe Me 6-Me H NH2 963 CH2CH2Ph OMe Me 6-Me H OH 964 CH2CH2Ph OMe Me 6-Me Me Me 965 CH2CH2Ph OMe Me 6-Me Me NH2 966 CH2CH2Ph OMe Me 6-Me Me OH 967 CH2CH2Ph OMe Me 7-Me H Me 968 CH2CH2Ph OMe Me 7-Me H NH2 969 CH2CH2Ph OMe Me 7-Me H OH 970 CH2CH2Ph OMe Me 7-Me Me Me 971 CH2CH2Ph OMe Me 7-Me Me NH2 972 CH2CH2Ph OMe Me 7-Me Me OH 973 H H Cl 5-H H Me 974 H H Cl 5-H H NH2 975 H H Cl 5-H H OH 976 H H Cl 5-H Me Me 977 H H Cl 5-H Me NH2 978 H H Cl 5-H Me OH 979 H H Cl 6-H H Me 980 H H Cl 6-H H NH2 981 H H Cl 6-H H OH 982 H H Cl 6-H Me Me 983 H H Cl 6-H Me NH2 984 H H Cl 6-H Me OH 985 H H Cl 7-H H Me 986 H H Cl 7-H H NH2 987 H H Cl 7-H H OH 988 H H Cl 7-H Me Me 989 H H Cl 7-H Me NH2 990 H H Cl 7-H Me OH 991 H H Cl 5-Cl H Me 992 H H Cl 5-Cl H NH2 993 H H Cl 5-Cl H OH 994 H H Cl 5-Cl Me Me 995 H H Cl 5-Cl Me NH2 996 H H Cl 5-Cl Me OH 997 H H Cl 6-Cl H Me 998 H H Cl 6-Cl H NH2 999 H H Cl 6-Cl H OH 1000 H H Cl 6-Cl Me Me

TABLE 26 Compound No. R1 R2 R3 R3′ R4 R5 1001 H H Cl 6-Cl Me NH2 1002 H H Cl 6-Cl Me OH 1003 H H Cl 7-Cl H Me 1004 H H Cl 7-Cl H NH2 1005 H H Cl 7-Cl H OH 1006 H H Cl 7-Cl Me Me 1007 H H Cl 7-Cl Me NH2 1008 H H Cl 7-Cl Me OH 1009 H H Cl 5-NH2 H Me 1010 H H Cl 5-NH2 H NH2 1011 H H Cl 5-NH2 H OH 1012 H H Cl 5-NH2 Me Me 1013 H H Cl 5-NH2 Me NH2 1014 H H Cl 5-NH2 Me OH 1015 H H Cl 6-NH2 H Me 1016 H H Cl 6-NH2 H NH2 1017 H H Cl 6-NH2 H OH 1018 H H Cl 6-NH2 Me Me 1019 H H Cl 6-NH2 Me NH2 1020 H H Cl 6-NH2 Me OH 1021 H H Cl 7-NH2 H Me 1022 H H Cl 7-NH2 H NH2 1023 H H Cl 7-NH2 H OH 1024 H H Cl 7-NH2 Me Me 1025 H H Cl 7-NH2 Me NH2 1026 H H Cl 7-NH2 Me OH 1027 H H Cl 5-Me H Me 1028 H H Cl 5-Me H NH2 1029 H H Cl 5-Me H OH 1030 H H Cl 5-Me Me Me 1031 H H Cl 5-Me Me NH2 1032 H H Cl 5-Me Me OH 1033 H H Cl 6-Me H Me 1034 H H Cl 6-Me H NH2 1035 H H Cl 6-Me H OH 1036 H H Cl 6-Me Me Me 1037 H H Cl 6-Me Me NH2 1038 H H Cl 6-Me Me OH 1039 H H Cl 7-Me H Me 1040 H H Cl 7-Me H NH2

TABLE 27 Compound No. R1 R2 R3 R3′ R4 R5 1041 H H Cl 7-Me H OH 1042 H H Cl 7-Me Me Me 1043 H H Cl 7-Me Me NH2 1044 H H Cl 7-Me Me OH 1045 H H NH2 5-H H Me 1046 H H NH2 5-H H NH2 1047 H H NH2 5-H H OH 1048 H H NH2 5-H Me Me 1049 H H NH2 5-H Me NH2 1050 H H NH2 5-H Me OH 1051 H H NH2 6-H H Me 1052 H H NH2 6-H H NH2 1053 H H NH2 6-H H OH 1054 H H NH2 6-H Me Me 1055 H H NH2 6-H Me NH2 1056 H H NH2 6-H Me OH 1057 H H NH2 7-H H Me 1058 H H NH2 7-H H NH2 1059 H H NH2 7-H H OH 1060 H H NH2 7-H Me Me 1061 H H NH2 7-H Me NH2 1062 H H NH2 7-H Me OH 1063 H H NH2 5-Cl H Me 1064 H H NH2 5-Cl H NH2 1065 H H NH2 5-Cl H OH 1066 H H NH2 5-Cl Me Me 1067 H H NH2 5-Cl Me NH2 1068 H H NH2 5-Cl Me OH 1069 H H NH2 6-Cl H Me 1070 H H NH2 6-Cl H NH2 1071 H H NH2 6-Cl H OH 1072 H H NH2 6-Cl Me Me 1073 H H NH2 6-Cl Me NH2 1074 H H NH2 6-Cl Me OH 1075 H H NH2 7-Cl H Me 1076 H H NH2 7-Cl H NH2 1077 H H NH2 7-Cl H OH 1078 H H NH2 7-Cl Me Me 1079 H H NH2 7-Cl Me NH2 1080 H H NH2 7-Cl Me OH

TABLE 28 Compound No. R1 R2 R3 R3′ R4 R5 1081 H H NH2 5-NH2 H Me 1082 H H NH2 5-NH2 H NH2 1083 H H NH2 5-NH2 H OH 1084 H H NH2 5-NH2 Me Me 1085 H H NH2 5-NH2 Me NH2 1086 H H NH2 5-NH2 Me OH 1087 H H NH2 6-NH2 H Me 1088 H H NH2 6-NH2 H NH2 1089 H H NH2 6-NH2 H OH 1090 H H NH2 6-NH2 Me Me 1091 H H NH2 6-NH2 Me NH2 1092 H H NH2 6-NH2 Me OH 1093 H H NH2 7-NH2 H Me 1094 H H NH2 7-NH2 H NH2 1095 H H NH2 7-NH2 H OH 1096 H H NH2 7-NH2 Me Me 1097 H H NH2 7-NH2 Me NH2 1098 H H NH2 7-NH2 Me OH 1099 H H NH2 5-Me H Me 1100 H H NH2 5-Me H NH2 1101 H H NH2 5-Me H OH 1102 H H NH2 5-Me Me Me 1103 H H NH2 5-Me Me NH2 1104 H H NH2 5-Me Me OH 1105 H H NH2 6-Me H Me 1106 H H NH2 6-Me H NH2 1107 H H NH2 6-Me H OH 1108 H H NH2 6-Me Me Me 1109 H H NH2 6-Me Me NH2 1110 H H NH2 6-Me Me OH 1111 H H NH2 7-Me H Me 1112 H H NH2 7-Me H NH2 1113 H H NH2 7-Me H OH 1114 H H NH2 7-Me Me Me 1115 H H NH2 7-Me Me NH2 1116 H H NH2 7-Me Me OH 1117 H H Me 5-H H Me 1118 H H Me 5-H H NH2 1119 H H Me 5-H H OH 1120 H H Me 5-H Me Me

TABLE 29 Compound No. R1 R2 R3 R3′ R4 R5 1121 H H Me 5-H Me NH2 1122 H H Me 5-H Me OH 1123 H H Me 6-H H Me 1124 H H Me 6-H H NH2 1125 H H Me 6-H H OH 1126 H H Me 6-H Me Me 1127 H H Me 6-H Me NH2 1128 H H Me 6-H Me OH 1129 H H Me 7-H H Me 1130 H H Me 7-H H NH2 1131 H H Me 7-H H OH 1132 H H Me 7-H Me Me 1133 H H Me 7-H Me NH2 1134 H H Me 7-H Me OH 1135 H H Me 5-Cl H Me 1136 H H Me 5-Cl H NH2 1137 H H Me 5-Cl H OH 1138 H H Me 5-Cl Me Me 1139 H H Me 5-Cl Me NH2 1140 H H Me 5-Cl Me OH 1141 H H Me 6-Cl H Me 1142 H H Me 6-Cl H NH2 1143 H H Me 6-Cl H OH 1144 H H Me 6-Cl Me Me 1145 H H Me 6-Cl Me NH2 1146 H H Me 6-Cl Me OH 1147 H H Me 7-Cl H Me 1148 H H Me 7-Cl H NH2 1149 H H Me 7-Cl H OH 1150 H H Me 7-Cl Me Me 1151 H H Me 7-Cl Me NH2 1152 H H Me 7-Cl Me OH 1153 H H Me 5-NH2 H Me 1154 H H Me 5-NH2 H NH2 1155 H H Me 5-NH2 H OH 1156 H H Me 5-NH2 Me Me 1157 H H Me 5-NH2 Me NH2 1158 H H Me 5-NH2 Me OH 1159 H H Me 6-NH2 H Me 1160 H H Me 6-NH2 H NH2

TABLE 30 Compound No. R1 R2 R3 R3′ R4 R5 1161 H H Me 6-NH2 H OH 1162 H H Me 6-NH2 Me Me 1163 H H Me 6-NH2 Me NH2 1164 H H Me 6-NH2 Me OH 1165 H H Me 7-NH2 H Me 1166 H H Me 7-NH2 H NH2 1167 H H Me 7-NH2 H OH 1168 H H Me 7-NH2 Me Me 1169 H H Me 7-NH2 Me NH2 1170 H H Me 7-NH2 Me OH 1171 H H Me 5-Me H Me 1172 H H Me 5-Me H NH2 1173 H H Me 5-Me H OH 1174 H H Me 5-Me Me Me 1175 H H Me 5-Me Me NH2 1176 H H Me 5-Me Me OH 1177 H H Me 6-Me H Me 1178 H H Me 6-Me H NH2 1179 H H Me 6-Me H OH 1180 H H Me 6-Me Me Me 1181 H H Me 6-Me Me NH2 1182 H H Me 6-Me Me OH 1183 H H Me 7-Me H Me 1184 H H Me 7-Me H NH2 1185 H H Me 7-Me H OH 1186 H H Me 7-Me Me Me 1187 H H Me 7-Me Me NH2 1188 H H Me 7-Me Me OH 1189 H H H 5-Cl H Me 1190 H H H 5-Cl H NH2 1191 H H H 5-Cl H OH 1192 H H H 5-Cl Me Me 1193 H H H 5-Cl Me NH2 1194 H H H 5-Cl Me OH 1195 H H H 6-Cl H Me 1196 H H H 6-Cl H NH2 1197 H H H 6-Cl H OH 1198 H H H 6-Cl Me Me 1199 H H H 6-Cl Me NH2 1200 H H H 6-Cl Me OH

TABLE 31 Compound No. R1 R2 R3 R3′ R4 R5 1201 H H H 7-Cl H Me 1202 H H H 7-Cl H NH2 1203 H H H 7-Cl H OH 1204 H H H 7-Cl Me Me 1205 H H H 7-Cl Me NH2 1206 H H H 7-Cl Me OH 1207 H H H 5-NH2 H Me 1208 H H H 5-NH2 H NH2 1209 H H H 5-NH2 H OH 1210 H H H 5-NH2 Me Me 1211 H H H 5-NH2 Me NH2 1212 H H H 5-NH2 Me OH 1213 H H H 6-NH2 H Me 1214 H H H 6-NH2 H NH2 1215 H H H 6-NH2 H OH 1216 H H H 6-NH2 Me Me 1217 H H H 6-NH2 Me NH2 1218 H H H 6-NH2 Me OH 1219 H H H 7-NH2 H Me 1220 H H H 7-NH2 H NH2 1221 H H H 7-NH2 H OH 1222 H H H 7-NH2 Me Me 1223 H H H 7-NH2 Me NH2 1224 H H H 7-NH2 Me OH 1225 H H H 5-Me H Me 1226 H H H 5-Me H NH2 1227 H H H 5-Me H OH 1228 H H H 5-Me Me Me 1229 H H H 5-Me Me NH2 1230 H H H 5-Me Me OH 1231 H H H 6-Me H Me 1232 H H H 6-Me H NH2 1233 H H H 6-Me H OH 1234 H H H 6-Me Me Me 1235 H H H 6-Me Me NH2 1236 H H H 6-Me Me OH 1237 H H H 7-Me H Me 1238 H H H 7-Me H NH2 1239 H H H 7-Me H OH 1240 H H H 7-Me Me Me

TABLE 32 Compound No. R1 R2 R3 R3′ R4 R5 1241 H H H 7-Me Me NH2 1242 H H H 7-Me Me OH 1243 H OMe Cl 5-H H Me 1244 H OMe Cl 5-H H NH2 1245 H OMe Cl 5-H H OH 1246 H OMe Cl 5-H Me Me 1247 H OMe Cl 5-H Me NH2 1248 H OMe Cl 5-H Me OH 1249 H OMe Cl 6-H H Me 1250 H OMe Cl 6-H H NH2 1251 H OMe Cl 6-H H OH 1252 H OMe Cl 6-H Me Me 1253 H OMe Cl 6-H Me NH2 1254 H OMe Cl 6-H Me OH 1255 H OMe Cl 7-H H Me 1256 H OMe Cl 7-H H NH2 1257 H OMe Cl 7-H H OH 1258 H OMe Cl 7-H Me Me 1259 H OMe Cl 7-H Me NH2 1260 H OMe Cl 7-H Me OH 1261 H OMe Cl 5-Cl H Me 1262 H OMe Cl 5-Cl H NH2 1263 H OMe Cl 5-Cl H OH 1264 H OMe Cl 5-Cl Me Me 1265 H OMe Cl 5-Cl Me NH2 1266 H OMe Cl 5-Cl Me OH 1267 H OMe Cl 6-Cl H Me 1268 H OMe Cl 6-Cl H NH2 1269 H OMe Cl 6-Cl H OH 1270 H OMe Cl 6-Cl Me Me 1271 H OMe Cl 6-Cl Me NH2 1272 H OMe Cl 6-Cl Me OH 1273 H OMe Cl 7-Cl H Me 1274 H OMe Cl 7-Cl H NH2 1275 H OMe Cl 7-Cl H OH 1276 H OMe Cl 7-Cl Me Me 1277 H OMe Cl 7-Cl Me NH2 1278 H OMe Cl 7-Cl Me OH 1279 H OMe Cl 5-NH2 H Me 1280 H OMe Cl 5-NH2 H NH2

TABLE 33 Compound No. R1 R2 R3 R3′ R4 R5 1281 H OMe Cl 5-NH2 H OH 1282 H OMe Cl 5-NH2 Me Me 1283 H OMe Cl 5-NH2 Me NH2 1284 H OMe Cl 5-NH2 Me OH 1285 H OMe Cl 6-NH2 H Me 1286 H OMe Cl 6-NH2 H NH2 1287 H OMe Cl 6-NH2 H OH 1288 H OMe Cl 6-NH2 Me Me 1289 H OMe Cl 6-NH2 Me NH2 1290 H OMe Cl 6-NH2 Me OH 1291 H OMe Cl 7-NH2 H Me 1292 H OMe Cl 7-NH2 H NH2 1293 H OMe Cl 7-NH2 H OH 1294 H OMe Cl 7-NH2 Me Me 1295 H OMe Cl 7-NH2 Me NH2 1296 H OMe Cl 7-NH2 Me OH 1297 H OMe Cl 5-Me H Me 1298 H OMe Cl 5-Me H NH2 1299 H OMe Cl 5-Me H OH 1300 H OMe Cl 5-Me Me Me 1301 H OMe Cl 5-Me Me NH2 1302 H OMe Cl 5-Me Me OH 1303 H OMe Cl 6-Me H Me 1304 H OMe Cl 6-Me H NH2 1305 H OMe Cl 6-Me H OH 1306 H OMe Cl 6-Me Me Me 1307 H OMe Cl 6-Me Me NH2 1308 H OMe Cl 6-Me Me OH 1309 H OMe Cl 7-Me H Me 1310 H OMe Cl 7-Me H NH2 1311 H OMe Cl 7-Me H OH 1312 H OMe Cl 7-Me Me Me 1313 H OMe Cl 7-Me Me NH2 1314 H OMe Cl 7-Me Me OH 1315 H OMe NH2 5-H H Me 1316 H OMe NH2 5-H H NH2 1317 H OMe NH2 5-H H OH 1318 H OMe NH2 5-H Me Me 1319 H OMe NH2 5-H Me NH2 1320 H OMe NH2 5-H Me OH

TABLE 34 Compound No. R1 R2 R3 R3′ R4 R5 1321 H OMe NH2 6-H H Me 1322 H OMe NH2 6-H H NH2 1323 H OMe NH2 6-H H OH 1324 H OMe NH2 6-H Me Me 1325 H OMe NH2 6-H Me NH2 1326 H OMe NH2 6-H Me OH 1327 H OMe NH2 7-H H Me 1328 H OMe NH2 7-H H NH2 1329 H OMe NH2 7-H H OH 1330 H OMe NH2 7-H Me Me 1331 H OMe NH2 7-H Me NH2 1332 H OMe NH2 7-H Me OH 1333 H OMe NH2 5-Cl H Me 1334 H OMe NH2 5-Cl H NH2 1335 H OMe NH2 5-Cl H OH 1336 H OMe NH2 5-Cl Me Me 1337 H OMe NH2 5-Cl Me NH2 1338 H OMe NH2 5-Cl Me OH 1339 H OMe NH2 6-Cl H Me 1340 H OMe NH2 6-Cl H NH2 1341 H OMe NH2 6-Cl H OH 1342 H OMe NH2 6-Cl Me Me 1343 H OMe NH2 6-Cl Me NH2 1344 H OMe NH2 6-Cl Me OH 1345 H OMe NH2 7-Cl H Me 1346 H OMe NH2 7-Cl H NH2 1347 H OMe NH2 7-Cl H OH 1348 H OMe NH2 7-Cl Me Me 1349 H OMe NH2 7-Cl Me NH2 1350 H OMe NH2 7-Cl Me OH 1351 H OMe NH2 5-NH2 H Me 1352 H OMe NH2 5-NH2 H NH2 1353 H OMe NH2 5-NH2 H OH 1354 H OMe NH2 5-NH2 Me Me 1355 H OMe NH2 5-NH2 Me NH2 1356 H OMe NH2 5-NH2 Me OH 1357 H OMe NH2 6-NH2 H Me 1358 H OMe NH2 6-NH2 H NH2 1359 H OMe NH2 6-NH2 H OH 1360 H OMe NH2 6-NH2 Me Me

TABLE 35 Compound No. R1 R2 R3 R3′ R4 R5 1361 H OMe NH2 6-NH2 Me NH2 1362 H OMe NH2 6-NH2 Me OH 1363 H OMe NH2 7-NH2 H Me 1364 H OMe NH2 7-NH2 H NH2 1365 H OMe NH2 7-NH2 H OH 1366 H OMe NH2 7-NH2 Me Me 1367 H OMe NH2 7-NH2 Me NH2 1368 H OMe NH2 7-NH2 Me OH 1369 H OMe NH2 5-Me H Me 1370 H OMe NH2 5-Me H NH2 1371 H OMe NH2 5-Me H OH 1372 H OMe NH2 5-Me Me Me 1373 H OMe NH2 5-Me Me NH2 1374 H OMe NH2 5-Me Me OH 1375 H OMe NH2 6-Me H Me 1376 H OMe NH2 6-Me H NH2 1377 H OMe NH2 6-Me H OH 1378 H OMe NH2 6-Me Me Me 1379 H OMe NH2 6-Me Me NH2 1380 H OMe NH2 6-Me Me OH 1381 H OMe NH2 7-Me H Me 1382 H OMe NH2 7-Me H NH2 1383 H OMe NH2 7-Me H OH 1384 H OMe NH2 7-Me Me Me 1385 H OMe NH2 7-Me Me NH2 1386 H OMe NH2 7-Me Me OH 1387 H OMe Me 5-H H Me 1388 H OMe Me 5-H H NH2 1389 H OMe Me 5-H H OH 1390 H OMe Me 5-H Me Me 1391 H OMe Me 5-H Me NH2 1392 H OMe Me 5-H Me OH 1393 H OMe Me 6-H H Me 1394 H OMe Me 6-H H NH2 1395 H OMe Me 6-H H OH 1396 H OMe Me 6-H Me Me 1397 H OMe Me 6-H Me NH2 1398 H OMe Me 6-H Me OH 1399 H OMe Me 7-H H Me 1400 H OMe Me 7-H H NH2

TABLE 36 Compound No. R1 R2 R3 R3′ R4 R5 1401 H OMe Me 7-H H OH 1402 H OMe Me 7-H Me Me 1403 H OMe Me 7-H Me NH2 1404 H OMe Me 7-H Me OH 1405 H OMe Me 5-Cl H Me 1406 H OMe Me 5-Cl H NH2 1407 H OMe Me 5-Cl H OH 1408 H OMe Me 5-Cl Me Me 1409 H OMe Me 5-Cl Me NH2 1410 H OMe Me 5-Cl Me OH 1411 H OMe Me 6-Cl H Me 1412 H OMe Me 6-Cl H NH2 1413 H OMe Me 6-Cl H OH 1414 H OMe Me 6-Cl Me Me 1415 H OMe Me 6-Cl Me NH2 1416 H OMe Me 6-Cl Me OH 1417 H OMe Me 7-Cl H Me 1418 H OMe Me 7-Cl H NH2 1419 H OMe Me 7-Cl H OH 1420 H OMe Me 7-Cl Me Me 1421 H OMe Me 7-Cl Me NH2 1422 H OMe Me 7-Cl Me OH 1423 H OMe Me 5-NH2 H Me 1424 H OMe Me 5-NH2 H NH2 1425 H OMe Me 5-NH2 H OH 1426 H OMe Me 5-NH2 Me Me 1427 H OMe Me 5-NH2 Me NH2 1428 H OMe Me 5-NH2 Me OH 1429 H OMe Me 6-NH2 H Me 1430 H OMe Me 6-NH2 H NH2 1431 H OMe Me 6-NH2 H OH 1432 H OMe Me 6-NH2 Me Me 1433 H OMe Me 6-NH2 Me NH2 1434 H OMe Me 6-NH2 Me OH 1435 H OMe Me 7-NH2 H Me 1436 H OMe Me 7-NH2 H NH2 1437 H OMe Me 7-NH2 H OH 1438 H OMe Me 7-NH2 Me Me 1439 H OMe Me 7-NH2 Me NH2 1440 H OMe Me 7-NH2 Me OH

TABLE 37 Compound No. R1 R2 R3 R3′ R4 R5 1441 H OMe Me 5-Me H Me 1442 H OMe Me 5-Me H NH2 1443 H OMe Me 5-Me H OH 1444 H OMe Me 5-Me Me Me 1445 H OMe Me 5-Me Me NH2 1446 H OMe Me 5-Me Me OH 1447 H OMe Me 6-Me H Me 1448 H OMe Me 6-Me H NH2 1449 H OMe Me 6-Me H OH 1450 H OMe Me 6-Me Me Me 1451 H OMe Me 6-Me Me NH2 1452 H OMe Me 6-Me Me OH 1453 H OMe Me 7-Me H Me 1454 H OMe Me 7-Me H NH2 1455 H OMe Me 7-Me H OH 1456 H OMe Me 7-Me Me Me 1457 H OMe Me 7-Me Me NH2 1458 H OMe Me 7-Me Me OH 1459 H OMe H 5-Cl H Me 1460 H OMe H 5-Cl H NH2 1461 H OMe H 5-Cl H OH 1462 H OMe H 5-Cl Me Me 1463 H OMe H 5-Cl Me NH2 1464 H OMe H 5-Cl Me OH 1465 H OMe H 6-Cl H Me 1466 H OMe H 6-Cl H NH2 1467 H OMe H 6-Cl H OH 1468 H OMe H 6-Cl Me Me 1469 H OMe H 6-Cl Me NH2 1470 H OMe H 6-Cl Me OH 1471 H OMe H 7-Cl H Me 1472 H OMe H 7-Cl H NH2 1473 H OMe H 7-Cl H OH 1474 H OMe H 7-Cl Me Me 1475 H OMe H 7-Cl Me NH2 1476 H OMe H 7-Cl Me OH 1477 H OMe H 5-NH2 H Me 1478 H OMe H 5-NH2 H NH2 1479 H OMe H 5-NH2 H OH 1480 H OMe H 5-NH2 Me Me

TABLE 38 Compound No. R1 R2 R3 R3′ R4 R5 1481 H OMe H 5-NH2 Me NH2 1482 H OMe H 5-NH2 Me OH 1483 H OMe H 6-NH2 H Me 1484 H OMe H 6-NH2 H NH2 1485 H OMe H 6-NH2 H OH 1486 H OMe H 6-NH2 Me Me 1487 H OMe H 6-NH2 Me NH2 1488 H OMe H 6-NH2 Me OH 1489 H OMe H 7-NH2 H Me 1490 H OMe H 7-NH2 H NH2 1491 H OMe H 7-NH2 H OH 1492 H OMe H 7-NH2 Me Me 1493 H OMe H 7-NH2 Me NH2 1494 H OMe H 7-NH2 Me OH 1495 H OMe H 5-Me H Me 1496 H OMe H 5-Me H NH2 1497 H OMe H 5-Me H OH 1498 H OMe H 5-Me Me Me 1499 H OMe H 5-Me Me NH2 1500 H OMe H 5-Me Me OH 1501 H OMe H 6-Me H Me 1502 H OMe H 6-Me H NH2 1503 H OMe H 6-Me H OH 1504 H OMe H 6-Me Me Me 1505 H OMe H 6-Me Me NH2 1506 H OMe H 6-Me Me OH 1507 H OMe H 7-Me H Me 1508 H OMe H 7-Me H NH2 1509 H OMe H 7-Me H OH 1510 H OMe H 7-Me Me Me 1511 H OMe H 7-Me Me NH2 1512 H OMe H 7-Me Me OH 1513 2-thienylethyl H Cl 5-H H Me 1514 2-thienylethyl H Cl 5-H H NH2 1515 2-thienylethyl H Cl 5-H H OH 1516 2-thienylethyl H Cl 5-H Me Me 1517 2-thienylethyl H Cl 5-H Me NH2 1518 2-thienylethyl H Cl 5-H Me OH 1519 2-thienylethyl H Cl 6-H H Me 1520 2-thienylethyl H Cl 6-H H NH2

TABLE 39 Compound No. R1 R2 R3 R3′ R4 R5 1521 2-thienylethyl H Cl 6-H H OH 1522 2-thienylethyl H Cl 6-H Me Me 1523 2-thienylethyl H Cl 6-H Me NH2 1524 2-thienylethyl H Cl 6-H Me OH 1525 2-thienylethyl H Cl 7-H H Me 1526 2-thienylethyl H Cl 7-H H NH2 1527 2-thienylethyl H Cl 7-H H OH 1528 2-thienylethyl H Cl 7-H Me Me 1529 2-thienylethyl H Cl 7-H Me NH2 1530 2-thienylethyl H Cl 7-H Me OH 1531 2-thienylethyl H Cl 5-Cl H Me 1532 2-thienylethyl H Cl 5-Cl H NH2 1533 2-thienylethyl H Cl 5-Cl H OH 1534 2-thienylethyl H Cl 5-Cl Me Me 1535 2-thienylethyl H Cl 5-Cl Me NH2 1536 2-thienylethyl H Cl 5-Cl Me OH 1537 2-thienylethyl H Cl 6-Cl H Me 1538 2-thienylethyl H Cl 6-Cl H NH2 1539 2-thienylethyl H Cl 6-Cl H OH 1540 2-thienylethyl H Cl 6-Cl Me Me 1541 2-thienylethyl H Cl 6-Cl Me NH2 1542 2-thienylethyl H Cl 6-Cl Me OH 1543 2-thienylethyl H Cl 7-Cl H Me 1544 2-thienylethyl H Cl 7-Cl H NH2 1545 2-thienylethyl H Cl 7-Cl H OH 1546 2-thienylethyl H Cl 7-Cl Me Me 1547 2-thienylethyl H Cl 7-Cl Me NH2 1548 2-thienylethyl H Cl 7-Cl Me OH 1549 2-thienylethyl H Cl 5-NH2 H Me 1550 2-thienylethyl H Cl 5-NH2 H NH2 1551 2-thienylethyl H Cl 5-NH2 H OH 1552 2-thienylethyl H Cl 5-NH2 Me Me 1553 2-thienylethyl H Cl 5-NH2 Me NH2 1554 2-thienylethyl H Cl 5-NH2 Me OH 1555 2-thienylethyl H Cl 6-NH2 H Me 1556 2-thienylethyl H Cl 6-NH2 H NH2 1557 2-thienylethyl H Cl 6-NH2 H OH 1558 2-thienylethyl H Cl 6-NH2 Me Me 1559 2-thienylethyl H Cl 6-NH2 Me NH2 1560 2-thienylethyl H Cl 6-NH2 Me OH

TABLE 40 Compound No. R1 R2 R3 R3′ R4 R5 1561 2-thienylethyl H Cl 7-NH2 H Me 1562 2-thienylethyl H Cl 7-NH2 H NH2 1563 2-thienylethyl H Cl 7-NH2 H OH 1564 2-thienylethyl H Cl 7-NH2 Me Me 1565 2-thienylethyl H Cl 7-NH2 Me NH2 1566 2-thienylethyl H Cl 7-NH2 Me OH 1567 2-thienylethyl H Cl 5-Me H Me 1568 2-thienylethyl H Cl 5-Me H NH2 1569 2-thienylethyl H Cl 5-Me H OH 1570 2-thienylethyl H Cl 5-Me Me Me 1571 2-thienylethyl H Cl 5-Me Me NH2 1572 2-thienylethyl H Cl 5-Me Me OH 1573 2-thienylethyl H Cl 6-Me H Me 1574 2-thienylethyl H Cl 6-Me H NH2 1575 2-thienylethyl H Cl 6-Me H OH 1576 2-thienylethyl H Cl 6-Me Me Me 1577 2-thienylethyl H Cl 6-Me Me NH2 1578 2-thienylethyl H Cl 6-Me Me OH 1579 2-thienylethyl H Cl 7-Me H Me 1580 2-thienylethyl H Cl 7-Me H NH2 1581 2-thienylethyl H Cl 7-Me H OH 1582 2-thienylethyl H Cl 7-Me Me Me 1583 2-thienylethyl H Cl 7-Me Me NH2 1584 2-thienylethyl H Cl 7-Me Me OH 1585 2-thienylethyl H NH2 5-H H Me 1586 2-thienylethyl H NH2 5-H H NH2 1587 2-thienylethyl H NH2 5-H H OH 1588 2-thienylethyl H NH2 5-H Me Me 1589 2-thienylethyl H NH2 5-H Me NH2 1590 2-thienylethyl H NH2 5-H Me OH 1591 2-thienylethyl H NH2 6-H H Me 1592 2-thienylethyl H NH2 6-H H NH2 1593 2-thienylethyl H NH2 6-H H OH 1594 2-thienylethyl H NH2 6-H Me Me 1595 2-thienylethyl H NH2 6-H Me NH2 1596 2-thienylethyl H NH2 6-H Me OH 1597 2-thienylethyl H NH2 7-H H Me 1598 2-thienylethyl H NH2 7-H H NH2 1599 2-thienylethyl H NH2 7-H H OH 1600 2-thienylethyl H NH2 7-H Me Me

TABLE 41 Compound No. R1 R2 R3 R3′ R4 R5 1601 2-thienylethyl H NH2 7-H Me NH2 1602 2-thienylethyl H NH2 7-H Me OH 1603 2-thienylethyl H NH2 5-Cl H Me 1604 2-thienylethyl H NH2 5-Cl H NH2 1605 2-thienylethyl H NH2 5-Cl H OH 1606 2-thienylethyl H NH2 5-Cl Me Me 1607 2-thienylethyl H NH2 5-Cl Me NH2 1608 2-thienylethyl H NH2 5-Cl Me OH 1609 2-thienylethyl H NH2 6-Cl H Me 1610 2-thienylethyl H NH2 6-Cl H NH2 1611 2-thienylethyl H NH2 6-Cl H OH 1612 2-thienylethyl H NH2 6-Cl Me Me 1613 2-thienylethyl H NH2 6-Cl Me NH2 1614 2-thienylethyl H NH2 6-Cl Me OH 1615 2-thienylethyl H NH2 7-Cl H Me 1616 2-thienylethyl H NH2 7-Cl H NH2 1617 2-thienylethyl H NH2 7-Cl H OH 1618 2-thienylethyl H NH2 7-Cl Me Me 1619 2-thienylethyl H NH2 7-Cl Me NH2 1620 2-thienylethyl H NH2 7-Cl Me OH 1621 2-thienylethyl H NH2 5-NH2 H Me 1622 2-thienylethyl H NH2 5-NH2 H NH2 1623 2-thienylethyl H NH2 5-NH2 H OH 1624 2-thienylethyl H NH2 5-NH2 Me Me 1625 2-thienylethyl H NH2 5-NH2 Me NH2 1626 2-thienylethyl H NH2 5-NH2 Me OH 1627 2-thienylethyl H NH2 6-NH2 H Me 1628 2-thienylethyl H NH2 6-NH2 H NH2 1629 2-thienylethyl H NH2 6-NH2 H OH 1630 2-thienylethyl H NH2 6-NH2 Me Me 1631 2-thienylethyl H NH2 6-NH2 Me NH2 1632 2-thienylethyl H NH2 6-NH2 Me OH 1633 2-thienylethyl H NH2 7-NH2 H Me 1634 2-thienylethyl H NH2 7-NH2 H NH2 1635 2-thienylethyl H NH2 7-NH2 H OH 1636 2-thienylethyl H NH2 7-NH2 Me Me 1637 2-thienylethyl H NH2 7-NH2 Me NH2 1638 2-thienylethyl H NH2 7-NH2 Me OH 1639 2-thienylethyl H NH2 5-Me H Me 1640 2-thienylethyl H NH2 5-Me H NH2

TABLE 42 Compound No. R1 R2 R3 R3′ R4 R5 1641 2-thienylethyl H NH2 5-Me H OH 1642 2-thienylethyl H NH2 5-Me Me Me 1643 2-thienylethyl H NH2 5-Me Me NH2 1644 2-thienylethyl H NH2 5-Me Me OH 1645 2-thienylethyl H NH2 6-Me H Me 1646 2-thienylethyl H NH2 6-Me H NH2 1647 2-thienylethyl H NH2 6-Me H OH 1648 2-thienylethyl H NH2 6-Me Me Me 1649 2-thienylethyl H NH2 6-Me Me NH2 1650 2-thienylethyl H NH2 6-Me Me OH 1651 2-thienylethyl H NH2 7-Me H Me 1652 2-thienylethyl H NH2 7-Me H NH2 1653 2-thienylethyl H NH2 7-Me H OH 1654 2-thienylethyl H NH2 7-Me Me Me 1655 2-thienylethyl H NH2 7-Me Me NH2 1656 2-thienylethyl H NH2 7-Me Me OH 1657 2-thienylethyl H Me 5-H H Me 1658 2-thienylethyl H Me 5-H H NH2 1659 2-thienylethyl H Me 5-H H OH 1660 2-thienylethyl H Me 5-H Me Me 1661 2-thienylethyl H Me 5-H Me NH2 1662 2-thienylethyl H Me 5-H Me OH 1663 2-thienylethyl H Me 6-H H Me 1664 2-thienylethyl H Me 6-H H NH2 1665 2-thienylethyl H Me 6-H H OH 1666 2-thienylethyl H Me 6-H Me Me 1667 2-thienylethyl H Me 6-H Me NH2 1668 2-thienylethyl H Me 6-H Me OH 1669 2-thienylethyl H Me 7-H H Me 1670 2-thienylethyl H Me 7-H H NH2 1671 2-thienylethyl H Me 7-H H OH 1672 2-thienylethyl H Me 7-H Me Me 1673 2-thienylethyl H Me 7-H Me NH2 1674 2-thienylethyl H Me 7-H Me OH 1675 2-thienylethyl H Me 5-Cl H Me 1676 2-thienylethyl H Me 5-Cl H NH2 1677 2-thienylethyl H Me 5-Cl H OH 1678 2-thienylethyl H Me 5-Cl Me Me 1679 2-thienylethyl H Me 5-Cl Me NH2 1680 2-thienylethyl H Me 5-Cl Me OH

TABLE 43 Compound No. R1 R2 R3 R3′ R4 R5 1681 2-thienylethyl H Me 6-Cl H Me 1682 2-thienylethyl H Me 6-Cl H NH2 1683 2-thienylethyl H Me 6-Cl H OH 1684 2-thienylethyl H Me 6-Cl Me Me 1685 2-thienylethyl H Me 6-Cl Me NH2 1686 2-thienylethyl H Me 6-Cl Me OH 1687 2-thienylethyl H Me 7-Cl H Me 1688 2-thienylethyl H Me 7-Cl H NH2 1689 2-thienylethyl H Me 7-Cl H OH 1690 2-thienylethyl H Me 7-Cl Me Me 1691 2-thienylethyl H Me 7-Cl Me NH2 1692 2-thienylethyl H Me 7-Cl Me OH 1693 2-thienylethyl H Me 5-NH2 H Me 1694 2-thienylethyl H Me 5-NH2 H NH2 1695 2-thienylethyl H Me 5-NH2 H OH 1696 2-thienylethyl H Me 5-NH2 Me Me 1697 2-thienylethyl H Me 5-NH2 Me NH2 1698 2-thienylethyl H Me 5-NH2 Me OH 1699 2-thienylethyl H Me 6-NH2 H Me 1700 2-thienylethyl H Me 6-NH2 H NH2 1701 2-thienylethyl H Me 6-NH2 H OH 1702 2-thienylethyl H Me 6-NH2 Me Me 1703 2-thienylethyl H Me 6-NH2 Me NH2 1704 2-thienylethyl H Me 6-NH2 Me OH 1705 2-thienylethyl H Me 7-NH2 H Me 1706 2-thienylethyl H Me 7-NH2 H NH2 1707 2-thienylethyl H Me 7-NH2 H OH 1708 2-thienylethyl H Me 7-NH2 Me Me 1709 2-thienylethyl H Me 7-NH2 Me NH2 1710 2-thienylethyl H Me 7-NH2 Me OH 1711 2-thienylethyl H Me 5-Me H Me 1712 2-thienylethyl H Me 5-Me H NH2 1713 2-thienylethyl H Me 5-Me H OH 1714 2-thienylethyl H Me 5-Me Me Me 1715 2-thienylethyl H Me 5-Me Me NH2 1716 2-thienylethyl H Me 5-Me Me OH 1717 2-thienylethyl H Me 6-Me H Me 1718 2-thienylethyl H Me 6-Me H NH2 1719 2-thienylethyl H Me 6-Me H OH 1720 2-thienylethyl H Me 6-Me Me Me

TABLE 44 Compound No. R1 R2 R3 R3′ R4 R5 1721 2-thienylethyl H Me 6-Me Me NH2 1722 2-thienylethyl H Me 6-Me Me OH 1723 2-thienylethyl H Me 7-Me H Me 1724 2-thienylethyl H Me 7-Me H NH2 1725 2-thienylethyl H Me 7-Me H OH 1726 2-thienylethyl H Me 7-Me Me Me 1727 2-thienylethyl H Me 7-Me Me NH2 1728 2-thienylethyl H Me 7-Me Me OH 1729 2-thienylethyl H H 5-Cl H Me 1730 2-thienylethyl H H 5-Cl H NH2 1731 2-thienylethyl H H 5-Cl H OH 1732 2-thienylethyl H H 5-Cl Me Me 1733 2-thienylethyl H H 5-Cl Me NH2 1734 2-thienylethyl H H 5-Cl Me OH 1735 2-thienylethyl H H 6-Cl H Me 1736 2-thienylethyl H H 6-Cl H NH2 1737 2-thienylethyl H H 6-Cl H OH 1738 2-thienylethyl H H 6-Cl Me Me 1739 2-thienylethyl H H 6-Cl Me NH2 1740 2-thienylethyl H H 6-Cl Me OH 1741 2-thienylethyl H H 7-Cl H Me 1742 2-thienylethyl H H 7-Cl H NH2 1743 2-thienylethyl H H 7-Cl H OH 1744 2-thienylethyl H H 7-Cl Me Me 1745 2-thienylethyl H H 7-Cl Me NH2 1746 2-thienylethyl H H 7-Cl Me OH 1747 2-thienylethyl H H 5-NH2 H Me 1748 2-thienylethyl H H 5-NH2 H NH2 1749 2-thienylethyl H H 5-NH2 H OH 1750 2-thienylethyl H H 5-NH2 Me Me 1751 2-thienylethyl H H 5-NH2 Me NH2 1752 2-thienylethyl H H 5-NH2 Me OH 1753 2-thienylethyl H H 6-NH2 H Me 1754 2-thienylethyl H H 6-NH2 H NH2 1755 2-thienylethyl H H 6-NH2 H OH 1756 2-thienylethyl H H 6-NH2 Me Me 1757 2-thienylethyl H H 6-NH2 Me NH2 1758 2-thienylethyl H H 6-NH2 Me OH 1759 2-thienylethyl H H 7-NH2 H Me 1760 2-thienylethyl H H 7-NH2 H NH2

TABLE 45 Compound No. R1 R2 R3 R3′ R4 R5 1761 2-thienylethyl H H 7-NH2 H OH 1762 2-thienylethyl H H 7-NH2 Me Me 1763 2-thienylethyl H H 7-NH2 Me NH2 1764 2-thienylethyl H H 7-NH2 Me OH 1765 2-thienylethyl H H 5-Me H Me 1766 2-thienylethyl H H 5-Me H NH2 1767 2-thienylethyl H H 5-Me H OH 1768 2-thienylethyl H H 5-Me Me Me 1769 2-thienylethyl H H 5-Me Me NH2 1770 2-thienylethyl H H 5-Me Me OH 1771 2-thienylethyl H H 6-Me H Me 1772 2-thienylethyl H H 6-Me H NH2 1773 2-thienylethyl H H 6-Me H OH 1774 2-thienylethyl H H 6-Me Me Me 1775 2-thienylethyl H H 6-Me Me NH2 1776 2-thienylethyl H H 6-Me Me OH 1777 2-thienylethyl H H 7-Me H Me 1778 2-thienylethyl H H 7-Me H NH2 1779 2-thienylethyl H H 7-Me H OH 1780 2-thienylethyl H H 7-Me Me Me 1781 2-thienylethyl H H 7-Me Me NH2 1782 2-thienylethyl H H 7-Me Me OH 1783 2-thienylethyl OMe Cl 5-H H Me 1784 2-thienylethyl OMe Cl 5-H H NH2 1785 2-thienylethyl OMe Cl 5-H H OH 1786 2-thienylethyl OMe Cl 5-H Me Me 1787 2-thienylethyl OMe Cl 5-H Me NH2 1788 2-thienylethyl OMe Cl 5-H Me OH 1789 2-thienylethyl OMe Cl 6-H H Me 1790 2-thienylethyl OMe Cl 6-H H NH2 1791 2-thienylethyl OMe Cl 6-H H OH 1792 2-thienylethyl OMe Cl 6-H Me Me 1793 2-thienylethyl OMe Cl 6-H Me NH2 1794 2-thienylethyl OMe Cl 6-H Me OH 1795 2-thienylethyl OMe Cl 7-H H Me 1796 2-thienylethyl OMe Cl 7-H H NH2 1797 2-thienylethyl OMe Cl 7-H H OH 1798 2-thienylethyl OMe Cl 7-H Me Me 1799 2-thienylethyl OMe Cl 7-H Me NH2 1800 2-thienylethyl OMe Cl 7-H Me OH

TABLE 46 Compound No. R1 R2 R3 R3′ R4 R5 1801 2-thienylethyl OMe Cl 5-Cl H Me 1802 2-thienylethyl OMe Cl 5-Cl H NH2 1803 2-thienylethyl OMe Cl 5-Cl H OH 1804 2-thienylethyl OMe Cl 5-Cl Me Me 1805 2-thienylethyl OMe Cl 5-Cl Me NH2 1806 2-thienylethyl OMe Cl 5-Cl Me OH 1807 2-thienylethyl OMe Cl 6-Cl H Me 1808 2-thienylethyl OMe Cl 6-Cl H NH2 1809 2-thienylethyl OMe Cl 6-Cl H OH 1810 2-thienylethyl OMe Cl 6-Cl Me Me 1811 2-thienylethyl OMe Cl 6-Cl Me NH2 1812 2-thienylethyl OMe Cl 6-Cl Me OH 1813 2-thienylethyl OMe Cl 7-Cl H Me 1814 2-thienylethyl OMe Cl 7-Cl H NH2 1815 2-thienylethyl OMe Cl 7-Cl H OH 1816 2-thienylethyl OMe Cl 7-Cl Me Me 1817 2-thienylethyl OMe Cl 7-Cl Me NH2 1818 2-thienylethyl OMe Cl 7-Cl Me OH 1819 2-thienylethyl OMe Cl 5-NH2 H Me 1820 2-thienylethyl OMe Cl 5-NH2 H NH2 1821 2-thienylethyl OMe Cl 5-NH2 H OH 1822 2-thienylethyl OMe Cl 5-NH2 Me Me 1823 2-thienylethyl OMe Cl 5-NH2 Me NH2 1824 2-thienylethyl OMe Cl 5-NH2 Me OH 1825 2-thienylethyl OMe Cl 6-NH2 H Me 1826 2-thienylethyl OMe Cl 6-NH2 H NH2 1827 2-thienylethyl OMe Cl 6-NH2 H OH 1828 2-thienylethyl OMe Cl 6-NH2 Me Me 1829 2-thienylethyl OMe Cl 6-NH2 Me NH2 1830 2-thienylethyl OMe Cl 6-NH2 Me OH 1831 2-thienylethyl OMe Cl 7-NH2 H Me 1832 2-thienylethyl OMe Cl 7-NH2 H NH2 1833 2-thienylethyl OMe Cl 7-NH2 H OH 1834 2-thienylethyl OMe Cl 7-NH2 Me Me 1835 2-thienylethyl OMe Cl 7-NH2 Me NH2 1836 2-thienylethyl OMe Cl 7-NH2 Me OH 1837 2-thienylethyl OMe Cl 5-Me H Me 1838 2-thienylethyl OMe Cl 5-Me H NH2 1839 2-thienylethyl OMe Cl 5-Me H OH 1840 2-thienylethyl OMe Cl 5-Me Me Me

TABLE 47 Compound No. R1 R2 R3 R3′ R4 R5 1841 2-thienylethyl OMe Cl 5-Me Me NH2 1842 2-thienylethyl OMe Cl 5-Me Me OH 1843 2-thienylethyl OMe Cl 6-Me H Me 1844 2-thienylethyl OMe Cl 6-Me H NH2 1845 2-thienylethyl OMe Cl 6-Me H OH 1846 2-thienylethyl OMe Cl 6-Me Me Me 1847 2-thienylethyl OMe Cl 6-Me Me NH2 1848 2-thienylethyl OMe Cl 6-Me Me OH 1849 2-thienylethyl OMe Cl 7-Me H Me 1850 2-thienylethyl OMe Cl 7-Me H NH2 1851 2-thienylethyl OMe Cl 7-Me H OH 1852 2-thienylethyl OMe Cl 7-Me Me Me 1853 2-thienylethyl OMe Cl 7-Me Me NH2 1854 2-thienylethyl OMe Cl 7-Me Me OH 1855 2-thienylethyl OMe NH2 5-H H Me 1856 2-thienylethyl OMe NH2 5-H H NH2 1857 2-thienylethyl OMe NH2 5-H H OH 1858 2-thienylethyl OMe NH2 5-H Me Me 1859 2-thienylethyl OMe NH2 5-H Me NH2 1860 2-thienylethyl OMe NH2 5-H Me OH 1861 2-thienylethyl OMe NH2 6-H H Me 1862 2-thienylethyl OMe NH2 6-H H NH2 1863 2-thienylethyl OMe NH2 6-H H OH 1864 2-thienylethyl OMe NH2 6-H Me Me 1865 2-thienylethyl OMe NH2 6-H Me NH2 1866 2-thienylethyl OMe NH2 6-H Me OH 1867 2-thienylethyl OMe NH2 7-H H Me 1868 2-thienylethyl OMe NH2 7-H H NH2 1869 2-thienylethyl OMe NH2 7-H H OH 1870 2-thienylethyl OMe NH2 7-H Me Me 1871 2-thienylethyl OMe NH2 7-H Me NH2 1872 2-thienylethyl OMe NH2 7-H Me OH 1873 2-thienylethyl OMe NH2 5-Cl H Me 1874 2-thienylethyl OMe NH2 5-Cl H NH2 1875 2-thienylethyl OMe NH2 5-Cl H OH 1876 2-thienylethyl OMe NH2 5-Cl Me Me 1877 2-thienylethyl OMe NH2 5-Cl Me NH2 1878 2-thienylethyl OMe NH2 5-Cl Me OH 1879 2-thienylethyl OMe NH2 6-Cl H Me 1880 2-thienylethyl OMe NH2 6-Cl H NH2

TABLE 48 Compound No. R1 R2 R3 R3′ R4 R5 1881 2-thienylethyl OMe NH2 6-Cl H OH 1882 2-thienylethyl OMe NH2 6-Cl Me Me 1883 2-thienylethyl OMe NH2 6-Cl Me NH2 1884 2-thienylethyl OMe NH2 6-Cl Me OH 1885 2-thienylethyl OMe NH2 7-Cl H Me 1886 2-thienylethyl OMe NH2 7-Cl H NH2 1887 2-thienylethyl OMe NH2 7-Cl H OH 1888 2-thienylethyl OMe NH2 7-Cl Me Me 1889 2-thienylethyl OMe NH2 7-Cl Me NH2 1890 2-thienylethyl OMe NH2 7-Cl Me OH 1891 2-thienylethyl OMe NH2 5-NH2 H Me 1892 2-thienylethyl OMe NH2 5-NH2 H NH2 1893 2-thienylethyl OMe NH2 5-NH2 H OH 1894 2-thienylethyl OMe NH2 5-NH2 Me Me 1895 2-thienylethyl OMe NH2 5-NH2 Me NH2 1896 2-thienylethyl OMe NH2 5-NH2 Me OH 1897 2-thienylethyl OMe NH2 6-NH2 H Me 1898 2-thienylethyl OMe NH2 6-NH2 H NH2 1899 2-thienylethyl OMe NH2 6-NH2 H OH 1900 2-thienylethyl OMe NH2 6-NH2 Me Me 1901 2-thienylethyl OMe NH2 6-NH2 Me NH2 1902 2-thienylethyl OMe NH2 6-NH2 Me OH 1903 2-thienylethyl OMe NH2 7-NH2 H Me 1904 2-thienylethyl OMe NH2 7-NH2 H NH2 1905 2-thienylethyl OMe NH2 7-NH2 H OH 1906 2-thienylethyl OMe NH2 7-NH2 Me Me 1907 2-thienylethyl OMe NH2 7-NH2 Me NH2 1908 2-thienylethyl OMe NH2 7-NH2 Me OH 1909 2-thienylethyl OMe NH2 5-Me H Me 1910 2-thienylethyl OMe NH2 5-Me H NH2 1911 2-thienylethyl OMe NH2 5-Me H OH 1912 2-thienylethyl OMe NH2 5-Me Me Me 1913 2-thienylethyl OMe NH2 5-Me Me NH2 1914 2-thienylethyl OMe NH2 5-Me Me OH 1915 2-thienylethyl OMe NH2 6-Me H Me 1916 2-thienylethyl OMe NH2 6-Me H NH2 1917 2-thienylethyl OMe NH2 6-Me H OH 1918 2-thienylethyl OMe NH2 6-Me Me Me 1919 2-thienylethyl OMe NH2 6-Me Me NH2 1920 2-thienylethyl OMe NH2 6-Me Me OH

TABLE 49 Compound No. R1 R2 R3 R3′ R4 R5 1921 2-thienylethyl OMe NH2 7-Me H Me 1922 2-thienylethyl OMe NH2 7-Me H NH2 1923 2-thienylethyl OMe NH2 7-Me H OH 1924 2-thienylethyl OMe NH2 7-Me Me Me 1925 2-thienylethyl OMe NH2 7-Me Me NH2 1926 2-thienylethyl OMe NH2 7-Me Me OH 1927 2-thienylethyl OMe Me 5-H H Me 1928 2-thienylethyl OMe Me 5-H H NH2 1929 2-thienylethyl OMe Me 5-H H OH 1930 2-thienylethyl OMe Me 5-H Me Me 1931 2-thienylethyl OMe Me 5-H Me NH2 1932 2-thienylethyl OMe Me 5-H Me OH 1933 2-thienylethyl OMe Me 6-H H Me 1934 2-thienylethyl OMe Me 6-H H NH2 1935 2-thienylethyl OMe Me 6-H H OH 1936 2-thienylethyl OMe Me 6-H Me Me 1937 2-thienylethyl OMe Me 6-H Me NH2 1938 2-thienylethyl OMe Me 6-H Me OH 1939 2-thienylethyl OMe Me 7-H H Me 1940 2-thienylethyl OMe Me 7-H H NH2 1941 2-thienylethyl OMe Me 7-H H OH 1942 2-thienylethyl OMe Me 7-H Me Me 1943 2-thienylethyl OMe Me 7-H Me NH2 1944 2-thienylethyl OMe Me 7-H Me OH 1945 2-thienylethyl OMe Me 5-Cl H Me 1946 2-thienylethyl OMe Me 5-Cl H NH2 1947 2-thienylethyl OMe Me 5-Cl H OH 1948 2-thienylethyl OMe Me 5-Cl Me Me 1949 2-thienylethyl OMe Me 5-Cl Me NH2 1950 2-thienylethyl OMe Me 5-Cl Me OH 1951 2-thienylethyl OMe Me 6-Cl H Me 1952 2-thienylethyl OMe Me 6-Cl H NH2 1953 2-thienylethyl OMe Me 6-Cl H OH 1954 2-thienylethyl OMe Me 6-Cl Me Me 1955 2-thienylethyl OMe Me 6-Cl Me NH2 1956 2-thienylethyl OMe Me 6-Cl Me OH 1957 2-thienylethyl OMe Me 7-Cl H Me 1958 2-thienylethyl OMe Me 7-Cl H NH2 1959 2-thienylethyl OMe Me 7-Cl H OH 1960 2-thienylethyl OMe Me 7-Cl Me Me

TABLE 50 Compound No. R1 R2 R3 R3′ R4 R5 1961 2-thienylethyl OMe Me 7-Cl Me NH2 1962 2-thienylethyl OMe Me 7-Cl Me OH 1963 2-thienylethyl OMe Me 5-NH2 H Me 1964 2-thienylethyl OMe Me 5-NH2 H NH2 1965 2-thienylethyl OMe Me 5-NH2 H OH 1966 2-thienylethyl OMe Me 5-NH2 Me Me 1967 2-thienylethyl OMe Me 5-NH2 Me NH2 1968 2-thienylethyl OMe Me 5-NH2 Me OH 1969 2-thienylethyl OMe Me 6-NH2 H Me 1970 2-thienylethyl OMe Me 6-NH2 H NH2 1971 2-thienylethyl OMe Me 6-NH2 H OH 1972 2-thienylethyl OMe Me 6-NH2 Me Me 1973 2-thienylethyl OMe Me 6-NH2 Me NH2 1974 2-thienylethyl OMe Me 6-NH2 Me OH 1975 2-thienylethyl OMe Me 7-NH2 H Me 1976 2-thienylethyl OMe Me 7-NH2 H NH2 1977 2-thienylethyl OMe Me 7-NH2 H OH 1978 2-thienylethyl OMe Me 7-NH2 Me Me 1979 2-thienylethyl OMe Me 7-NH2 Me NH2 1980 2-thienylethyl OMe Me 7-NH2 Me OH 1981 2-thienylethyl OMe Me 5-Me H Me 1982 2-thienylethyl OMe Me 5-Me H NH2 1983 2-thienylethyl OMe Me 5-Me H OH 1984 2-thienylethyl OMe Me 5-Me Me Me 1985 2-thienylethyl OMe Me 5-Me Me NH2 1986 2-thienylethyl OMe Me 5-Me Me OH 1987 2-thienylethyl OMe Me 6-Me H Me 1988 2-thienylethyl OMe Me 6-Me H NH2 1989 2-thienylethyl OMe Me 6-Me H OH 1990 2-thienylethyl OMe Me 6-Me Me Me 1991 2-thienylethyl OMe Me 6-Me Me NH2 1992 2-thienylethyl OMe Me 6-Me Me OH 1993 2-thienylethyl OMe Me 7-Me H Me 1994 2-thienylethyl OMe Me 7-Me H NH2 1995 2-thienylethyl OMe Me 7-Me H OH 1996 2-thienylethyl OMe Me 7-Me Me Me 1997 2-thienylethyl OMe Me 7-Me Me NH2 1998 2-thienylethyl OMe Me 7-Me Me OH 1999 2-thienylethyl OMe H 5-Cl H Me 2000 2-thienylethyl OMe H 5-Cl H NH2

TABLE 51 Compound No. R1 R2 R3 R3′ R4 R5 2001 2-thienylethyl OMe H 5-Cl H OH 2002 2-thienylethyl OMe H 5-Cl Me Me 2003 2-thienylethyl OMe H 5-Cl Me NH2 2004 2-thienylethyl OMe H 5-Cl Me OH 2005 2-thienylethyl OMe H 6-Cl H Me 2006 2-thienylethyl OMe H 6-Cl H NH2 2007 2-thienylethyl OMe H 6-Cl H OH 2008 2-thienylethyl OMe H 6-Cl Me Me 2009 2-thienylethyl OMe H 6-Cl Me NH2 2010 2-thienylethyl OMe H 6-Cl Me OH 2011 2-thienylethyl OMe H 7-Cl H Me 2012 2-thienylethyl OMe H 7-Cl H NH2 2013 2-thienylethyl OMe H 7-Cl H OH 2014 2-thienylethyl OMe H 7-Cl Me Me 2015 2-thienylethyl OMe H 7-Cl Me NH2 2016 2-thienylethyl OMe H 7-Cl Me OH 2017 2-thienylethyl OMe H 5-NH2 H Me 2018 2-thienylethyl OMe H 5-NH2 H NH2 2019 2-thienylethyl OMe H 5-NH2 H OH 2020 2-thienylethyl OMe H 5-NH2 Me Me 2021 2-thienylethyl OMe H 5-NH2 Me NH2 2022 2-thienylethyl OMe H 5-NH2 Me OH 2023 2-thienylethyl OMe H 6-NH2 H Me 2024 2-thienylethyl OMe H 6-NH2 H NH2 2025 2-thienylethyl OMe H 6-NH2 H OH 2026 2-thienylethyl OMe H 6-NH2 Me Me 2027 2-thienylethyl OMe H 6-NH2 Me NH2 2028 2-thienylethyl OMe H 6-NH2 Me OH 2029 2-thienylethyl OMe H 7-NH2 H Me 2030 2-thienylethyl OMe H 7-NH2 H NH2 2031 2-thienylethyl OMe H 7-NH2 H OH 2032 2-thienylethyl OMe H 7-NH2 Me Me 2033 2-thienylethyl OMe H 7-NH2 Me NH2 2034 2-thienylethyl OMe H 7-NH2 Me OH 2035 2-thienylethyl OMe H 5-Me H Me 2036 2-thienylethyl OMe H 5-Me H NH2 2037 2-thienylethyl OMe H 5-Me H OH 2038 2-thienylethyl OMe H 5-Me Me Me 2039 2-thienylethyl OMe H 5-Me Me NH2 2040 2-thienylethyl OMe H 5-Me Me OH

TABLE 52 Compound No. R1 R2 R3 R3′ R4 R5 2041 2-thienylethyl OMe H 6-Me H Me 2042 2-thienylethyl OMe H 6-Me H NH2 2043 2-thienylethyl OMe H 6-Me H OH 2044 2-thienylethyl OMe H 6-Me Me Me 2045 2-thienylethyl OMe H 6-Me Me NH2 2046 2-thienylethyl OMe H 6-Me Me OH 2047 2-thienylethyl OMe H 7-Me H Me 2048 2-thienylethyl OMe H 7-Me H NH2 2049 2-thienylethyl OMe H 7-Me H OH 2050 2-thienylethyl OMe H 7-Me Me Me 2051 2-thienylethyl OMe H 7-Me Me NH2 2052 2-thienylethyl OMe H 7-Me Me OH

The compounds of Formula (I) can be obtained by, for example, condensing a ketone (III) as a starting material with o-aminobenzaldehyde derivative (IVa), o-aminoacetophenone (IVb) or o-aminobenzonitrile (IVc) in a solvent in the presence of an acid catalyst, in accordance with the method described in Japanese Laid-open Patent Application (Kokai) No. 4-275288 or WO99/02157. In this case, by using an optically active compound as the starting material, an optically active compound can be obtained (Scheme 1).

The fact that the isoquinoline derivatives of Formula (I) are effective for therapy and/or prevention of memory disorder may be confirmed by a behavioral pharmacological method using animals as described in Examples. More specifically, the passive avoidance test, the conditioned active avoidance test, or the spacial memory test using a water maize or a radial type maze are often used to develop an anti-dementia drug.

The compounds of the present invention may be used as pharmaceuticals useful for therapy and/or prevention of dementia accompanying learning disability and/or memory disorder. Especially, they may be used for therapy and/or prevention of dementia accompanying memory disorder caused by a cerebrovascular disease, neurodegererantive disease, endocrine disease, nutritional or metabolic disorder, anoxic encephalopathy, tumor, infectious disease, disorder of metabolism of a metal, or drug addiction. Examples of cerebrovascular diseases exhibiting dementia include cerebral infarction, cerebral hemorrhage, multiinfarct dementia, moyamoya disease, intracranial arteriovenous malformation, systemic lupus erythematodes (SLE) and angitis such as temporal arteritis. Examples of neurodegeretative diseases accompanying dementia include Alzheimer's disease, Pick's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy, Shy-Drager syndrome, Ramsay Hunt's syndrome and familial basal ganglia calcification. Examples of endocrine diseases include hypothyroidism, hypoparathyroidism syndrome, Cushing's disease, Addison's disease and recurrent hypoglycemic attack. Examples of nutritional or metabolic disorder include Wernicke encephalitis, pellagra encephalopathy, vitamin B12 deficiency, chronic metabolic disorders such as hepatic insufficiency and renal insufficiency, and hyponatremia. Examples of anoxic encephalopathy include carbon monoxide poisoning. Examples of tumors include cerebral tumor and meningitis carcinomatosa. Examples of infectious diseases include cerebral meningitis, encephalitides, cerebral tumor, slow virus disease, AIDS and neurosyphilis. Examples of other diseases which exhibit dementia include normal pressure hydrocephalus, chronic subdural hematoma, brain contusion, myotonic dystrophy and mitochondrial myopathy. The application of the compounds of the present invention is not restricted to these diseases.

The agent for improving learning and/or memory according to the present invention may be used in combination with one or more of other drugs for therapy and/or prevention of diseases exhibiting dementia (e.g., cerebrovascular diseases, neurodegeretative diseases, endocrine diseases, nutritional or metabolic disorder, anoxic encephalopathy, malignant tumors and infectious diseases) and drugs used for problamatic behavior accompanied by dementia (night delirium, night restlessness, depression, sleep disorder and personality change).

Examples of the drugs for prevention and/or therapy of cerebrovascular diseases include cerebral circulation metabolism activators such as ATP, cytochrome c, meclofenoxate hydrochloride, idebenone, propentofylline, γ-aminobutyric acid, γ-amino-β-hydroxybutyric acid, calcium hopantenate, anirasetam, amantadine hydrochloride, lisuride maleate, bifemelane hydrochloride, indeloxazine hydrochloride, dihydroergotoxine mesylate, ifenprodil tartrate, moxisylyte hydrochloride, bencylane fumarate, brovincamine fumarate, ibudilast, vinpocetine, nicergoline, cinepazide maleate, pentoxifylline, trapidil, dilazep hydrochloride, flunarizine hydrochloride, cinnarizine, nicardipine hydrochloride, nilvadipine and kallidinogenase; antihypertensive drugs such as chlorothiazide, ethacrynic acid, clonidine, reserpine, propranolol, prazosin, hydralazine, papaverine, captopril and nifedipine; anticoagulant drugs such as warfarin; thrombolytic agents such as urokinase; anti-platelet agents such as ozagrel and beraprost.

Examples of drugs for prevention and/or therapy of neurodegenerative diseases include anti-dementia drugs such as tacrine, therapeutic agents for Parkinson's disease such as levodopa, benztropine, deprenyl, biperiden, promethazine and diphenhydramine, as well as the above-mentioned cerebral circulation metabolism activators.

Examples of the drugs for prevention and/or therapy of problematic behavior accompanied by dementia include antidepressant drugs such as amitriptyline, dothiepin, lofepramine, imipramine, fluoxetine, fluvoxamine, mianserin, trazodone, maprotiline and safrazine; antianxiety agents such as diazepam and meprobamate; hypnotics such as haloxazolam and triazolam; and neuroplegics such as chlorpromazine, thioridazine and fluphenazine.

Examples of the drugs for prevention and/or therapy of endocrine diseases include antithyroid drugs (e.g., thionamide, methimazole and iodine), antidiabetic drugs (e.g., insulin formulation, tolbutamide, glipizide, metformin and acarbose), adenocorticotropic hormones (e.g., glucocorticoids such as hydrocortisone, prednisolone, betamethasone, dexamethasone; and mineral corticoids such as aldosterone), and anti-adenocorticotropic hormones (e.g., metyrapone).

Examples of the drugs for prevention and/or therapy of malignant tumors include alkylating agents such as cyclophosphamide and chlorambucil; cytotoxic antibiotics such as doxorubicin; vinca alkaloids such as vincristin; antimetabolites such as methotrexate, fluorouracil, cytarabine and mercaptopurine; and cisplatin.

When the agent for improving learning and/or memory according to the present invention is clinically used, the agent may be in the form of free base or salt thereof per se, or may be admixed with one or more additives such as vehicles, stabilizers, preservatives, buffer agents, solubilizers, emulsifiers, diluents and isotonic agents. The agent may be administered either orally or parenterally. The agent may be formulated in the form of injection solution, tablets, solution, capsules, granules, powder or the like. These formulations may be produced by known formulation techniques. The dose may be appropriately selected depending on the symptoms, age and bodyweight of the patient, and administration route. The dose of the effective component for an adult may be 0.0001 mg to 10 g per day, preferably 0.001 mg to 1 g per day, and the agent may be administered in one time or in several times.

EXAMPLES

The present invention will now be described concretely referring to Reference Examples and Examples.

Reference Example 1 (4aR, 12aR)-2-methyl-4a-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a-octahydro-quinoline[2,3-g]isoquinoline 1 Methanesulfonic Acid Salt

This compound was synthesized by the method described in WO99/02157.

Reference Example 2 2-methyl-4aα-(3-methoxyphenyl)-11-methyl-1,2,3,4,4a,5,12,12aβ-octahydro-quinolino[2,3-g]isoquinoline 2

To 5 mL of acetic acid, 150 mg (0.55 mmol) of 2-methyl-4α-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-octahydroisoquinoline and 100 mg (0.74 mmol) of o-aminoacetophenone were added and the mixture was heated to reflux for 3 hours. After allowing the mixture to cool, saturated aqueous sodium hydrogen carbonate solution was added and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The obtained residue was subjected to silica gel column chromatography (chlroform:methanol:28% aqueous ammonia=20:1:0.1 to 10:1:0.1) for purification to obtain 211 mg of the captioned compound (yield: 100%).

Reference Example 3 2-methyl-4aα-(3-hydroxyphenyl)-11-methyl-1,2,3,4,4a,5,12,12aβ-octahydro-quinolino[2,3-g]isoquinoline 3 Hydrochloric Acid Salt

In 7 mL of DMF solvent, 210 mg (0.56 mmol) of 2-methyl-4aα-(3-methoxyphenyl)-11-methyl-1,2,3,4,4a,5,12,12aβ-octahydro-quinolino[2,3-g]isoquinoline obtained in Reference Example 2 and 0.29 mL (3.20 mmol) of n-propanethiol were dissolved under argon atmosphere. To the mixture, 320 mg (2.85 mmol) of potassium-t-butoxide was added and the mixture was heated at 120° C. for 20 hours under stirring. To the mixture, 4 mL of 1N hydrochloric acid was added while cooling the mixture in ice to make the mixture acidic, and then saturated aqueous sodium hydrogen carbonate solution was added to make the mixture again basic, followed by extraction of the resulting mixture with chloroform: methanol (4:1) mixture. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration of the resulting product. The obtained residue was recrystallized from dichloromethane-methanol mixture to obtain 131 mg of the captioned compound (yield: 65%). The obtained product was suspended in methanol and hydrochloric acid was added to convert the compound to a salt. After concentration of the product, ether was added and solids were collected by filtration to obtain 143 mg of hydrochloric acid salt of the captioned compound.

Reference Example 4 2-methyl-4aα-(3-methoxphenyl)-11-amino-1,2,3,4,4a,5,12,12aβ-octahydro-quinolino[2,3-g]isoquinoline 4

To 5 mL of acetic acid, 150 mg (0.55 mmol) of 2-methyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a, 5,6,7,8,8aβ-octahydroisoquinoline and 130 mg (1.10 mmol) of o-aminobenzonitrile were added, and the mixture was heated to reflux for 44 hours. After allowing the mixture to cool, saturated aqueous sodium hydrogen carbonate solution was added, and the resulting mixture was extracted with chloroform:methanol (4:1) mixture. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, followed by concentration of the obtained product. The obtained residue was subjected to amine-coated silica gel column chromatography (chloroform:methanol=50:1) for purification to obtain 83 mg of the captioned compound (yield: 41%).

Reference Example 5 2-methyl-4aα-(3-hydroxyphenyl)-11-amino-1,2,3,4,4a,5,12,12aβ-octahydro-quinolino[2,3-g]isoquinoline 5 Hydrochloric Acid Salt

In 7 mL of DMF solvent, 83 mg (0.22 mmol) of 2-methyl-4aα-(3-methoxphenyl)-11-amino-1,2,3,4,4a,5,12,12aβ-octahydro-quinolino[2,3-g]isoquinoline obtained in Reference Example 4 and 0.10 mL (1.060 mmol) of n-propanethiol were dissolved under argon atmosphere. To the mixture, 106 mg (0.95 mmol) of potassium-t-butoxide was added and the mixture was heated at 120° C. for 20 hours under stirring. To the mixture, 4 mL of 1N hydrochloric acid was added while cooling the mixture in ice to make the mixture acidic, and then saturated aqueous sodium hydrogen carbonate solution was added to make the mixture again basic, followed by extraction of the resulting mixture with chloroform:methanol (4:1) mixture. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration of the resulting product. The obtained residue was recrystallized from dichloromethane-methanol mixture to obtain 35 mg of the captioned compound (yield: 44%). The obtained product was suspended in methanol and hydrochloric acid was added to convert the compound to a salt. After concentration of the product, ether was added and solids were collected by filtration to obtain 40 mg of hydrochloric acid salt of the captioned compound.

Reference Example 6 (+)-7,9-dibromo-4a-(3-methoxyphenyl)-2-methyl-1,2,3,4,4a,5,12,12a-octahydro-quinoline[2,3 g]isoquinoline 6

In ethanol, 382.4 mg of (+)-4a-(3-methoxyphenyl)-2-methyl-6-oxo-1,2,3,4,4a,5,6,7,8,8a-octahydroisoquinoline and 1.95 g of 2-amino-3,5-dibromobenzaldehyde were dissolved, and 0.454 ml of methanesulfonic acid was added, followed by heating the resulting mixture to reflux for 2 hours. After allowing the mixture to cool, saturated aqueous sodium hydrogen carbonate solution was added and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the obtained residue was purified by silica gel column chromatography (chloroform:methanol=40:1) to obtain 683.7 mg of the captioned compound (yield: 95%).

Reference Example 7 (+)-7,9-dibromo-4a-(3-hydroxyphenyl)-2-methyl-1,2,3,4,4a,5,12,12a-octahydro-quinoline[2,3 g]isoquinoline 7

In 15 ml of dichloromethane, 669.6 mg of (+)-7,9-dibromo-4a-(3-methoxyphenyl)-2-methyl-1,2,3,4,4a,5,12,12a-octahydro-quinoline[2,3 g]isoquinoline obtained in Reference Example 6 was dissolved, and 6.49 ml of boron tribromide solution in dichloromethane (1 mol/l) was added dropwise while cooling the mixture in ice. After stirring the mixture at 0° C. for 4 hours, saturated aqueous sodium hydrogen carbonate solution was added and the resulting mixture was vigorously stirred for 30 minutes at room temperature. After extracting the mixture with chloroform, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the obtained residue was purified by silica gel column chromatography (chloroform:methanol=20:1-5:1) to obtain 381.5 mg of the captioned compound (yield: 59%).

Reference Example 8 (+)-7,9-dibromo-4a-(3-hydroxyphenyl)-2-methyl-1,2,3,4,4a,5,12,12a-octahydro-quinoline[2,3 g]isoquinoline Methanesulfonic Acid Salt 8

In methanol, 381.5 mg of (+)-7,9-dibromo-4a-(3-hydroxyphenyl)-2-methyl-1,2,3,4,4a,5,12,12a-octahydro-quinoline[2,3 g]isoquinoline obtained in Reference Example 7 was suspended, and 1.522 ml of methanesulfonic acid was added, followed by stirring the mixture for 10 minutes. The reaction solution was concentrated and the obtained residue was repreciptated from methanol, ethyl acetate and diethylether to obtain 348.2 mg of the captioned compound.

Reference Example 9 (+)-9-fluoro-4a-(3-methoxyphenyl)-2-methyl-1,2,3,4,4a,5,12,12a-octahydro-quinoline[2,3 g]isoquinoline 9

A mixture of 380.3 mg of (+)-4a-(3-methoxyphenyl)-2-methyl-6-oxo-1,2,3,4,4a,5,6,7,8,8a-octahydroisoquinoline and 0.924 ml of dimethylformamide dimethylacetal in toluene solvent was heated to reflux for 5.5 hours. After allowing the mixture to cool, the reaction solution was concentrated and dried under reduced pressure. The residue was dissolved in 8 ml of xylene, and 0.395 ml of 4-fluoroaniline and 0.536 ml of trifluoroacetic acid were added, followed by heating the resulting mixture to reflux for 11 hours. After allowing the mixture to cool, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the obtained residue was purified by silica gel column chromatography (chlroform:methanol=15:1-10:1) to obtain 249.9 mg of the captioned compound (yield: 48%).

Reference Example 10 (+)-9-fluoro-4a-(3-hydroxyphenyl)-2-methyl-1,2,3,4,4a,5,12,12a-octahydro-quinoline[2,3 g]isoquinoline 10

In 9 ml of dichloromethane, 249.9 mg of (+)-9-fluoro-4a-(3-methoxyphenyl)-2-methyl-1,2,3,4,4a,5,12,12a-octahydro-quinoline[2,3 g]isoquinoline obtained in Reference Example 9 was dissolved, and 3.32 ml of 1N boron tribromide solution in dichloromethane was added dropwise while cooling the mixture in ice, and then the resulting mixture was stirred for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was slowly added and the mixture was vigorously stirred for 30 minutes. The reaction solution was extracted with chloroform and the organic layer was washed with brine, followed by drying over anhydrous sodium sulfate. After filtration and concentration, the obtained residue was purified by silica gel column chromatography (chlroform:methanol:isopropylamine=97:2.7:0.3), and then by thin layer chromatography (chloroform:chloroform saturated with ammonia=1:1) to obtain 65 mg of the captioned compound (yield: 27%).

Reference Example 11 (+)-9-fluoro-4a-(3-hydroxyphenyl)-2-methyl-1,2,3,4,4a,5,12,12a-octahydro-quinoline[2,3 g]isoquinoline Tartaric Acid Salt 11

In 2 ml of methanol, 48.6 mg of (+)-9-fluoro-4a-(3-hydroxyphenyl)-2-methyl-1,2,3,4,4a,5,12,12a-octahydro-quinoline[2,3 g]isoquinoline obtained in Reference Example 10 was dissolved, and 40.2 mg of L-tartaric acid was added, followed by stirring the mixture for 10 minutes. After concentrating the reaction solution, the residue was reprecipitated from methanol-ethyl acetate mixed solvent to obtain 57.0 mg of the captioned compound.

The chemical structure, acid addition salts and various spectra data of the Compounds 2 to 11 described in the Reference Examples are shown in Tables 53 to 56 below.

TABLE 53 Yield (%) NMR (ppm) (300 MHz CDCl3) m.p. (° C.)

2.0(1H, m), 2.16(1H, m), 2.3(1H, m), 2.41(3H, s), 2.51 (3H, s), 2.7(2H, m), 2.82(1H, t, J=11.5Hz), 3.06(3H, m), 3.14(1H, d, J=16.5Hz), 3.68(3H, s), 3.74(1H, d, J=16.5Hz), 6.67(1H, m), 7.06(1H, m), 7.42(1H, m), 7.55(1H, m), 7.9 (2H, m) # Elementary Analysis Composition Formula Calcd. Found IR (cm⁻¹) (KBr) 2928, 2798, 1607, 1582, 1487, 1431, 1288, 1230 Mass (EI) 372 (M+) (data of salt-free compound) Yield (%) NMR (ppm) (500 MHz, D2O) m.p.(° C.)

2.27(1H, dt, J=14.5, 3.4Hz), 2.68(1H, t, J=11.7Hz), 2.81(3H, s), 2.97(1H, m), 3.3(2H, m), 3.4-3.6(4H, m), 3.68(1H, dd, J=12.7, 3.2Hz), 3.95(1H, d, J=17.0Hz), 6.54(1H, dd, J=8.1, 2.0Hz), 6.95(1H, d, J=7.9Hz), 7.01(1H, m), 7.06(1H, t, J=8.1Hz), 7.83(1H, t, J=7.7Hz), 7.99(1H, t, J=7.7Hz), 8.22 (1H, d, J=8.5Hz), 8.39(1H, d, J=8.7Hz) # Elementary Analysis Composition Formula C24H26N2O/2HCl/0.6H2O Calcd. C: 65.19, H: 6.66, N: 6.33, Cl: 16.03 Found C: 65.05, H: 6.90, N: 6.31, Cl: 16.13 IR (cm⁻¹) Mass (EI) 358 (M+)

TABLE 54 Yield (%) NMR (ppm) (300 MHz, CDCl3) m.p. (° C.)

2.0(1H, m), 2.1(1H, m), 2.28(1H, m), 2.38(3H, s), 2.6-2.9 (5H, m), 2.97(1H, dd, J=11.0, 3.3Hz), 3.05(1H, d, J=16.5Hz), 3.64(1H, d, J=16.8Hz), 3.67(3H, s), 4.58(2H, brs), 6.58(1H, m), 7.05(3H, m), 7.32(1H, dt, J=7.5, 1.2Hz), 7.51 (1H, dt, J=7.5, 1.2Hz), 7.61(1H, dd, J=8.5, 0.5Hz), 7.82(1H, dd, J=8.5, 0.5Hz) # Elementary Analysis Composition Formula Calcd. Found IR (cm⁻¹) (KBr) 3058, 2918, 2800, 1651, 1578, 1502, 1439, 1243 Mass (EI) 373 (M+) Yield (%) NMR (ppm) (500 MHz, D2O) m.p. (° C.)

2.21 (1H, dt, J=14.5, 2.5Hz) 2.49(1H, d, J=12.5Hz), 2.67(1H, t, J=12.7Hz), 2.84(3H, s), 2.8-2.9(3H, m), 3.17(1H,d, J=16.9Hz), 3.4-3.5(3H, m), 3.60(1H, d, J=10.3Hz), 6.58(2H, m), 6.90(2H, m), 7.09(1H, t, J=8.1Hz), 7.61(1H, d, J=7.3, 1.6Hz), 7.86(2H, m), 8.47(1H, d, J=8.5Hz) # Elementary Analysis Composition Formula Calcd. Found IR (cm⁻¹) Mass (EI) 359 (M+)

TABLE 55 NMR (ppm) (300 MHz, CDCl3) m.p. (° C.)

2.03-2.09(1H, m), 2.17-2.31(2H, m), 2.40(3H, s), 2.62-2.72 (2H, m), 2.78(1H, t, J=11.5Hz), 3.00(1H, dd, J=2.7, 11.0Hz), 3.08-3.30(3H, m), 3.67(3H, s), 3.83(1H, d, J=16.8Hz), 6.57-6.60(1H, m), 7.03(1H, s), 7.05(1H, s), 7.09(1H, t, J=8.5Hz), 7.58-7.72(2H, brm), 7.92(1H, s) # Elementary Analysis Composition Formula Calcd. Found IR (cm⁻¹) Mass

2.14(1H, dt, J = 3.6, 14.3Hz), 2.30(1H, d, J=14.6Hz), 2.43(1H, brt, J=11.8Hz), 2.52(3H, s), 2.75-2.84(1H, m), 2.96-3.21(6H, m), 3.76(1H, d, J=17.0Hz), 6.48(1H, td, J=1.6, 8.0Hz), 6.81-6.86(2H, m), 6.93(1H, t, J=7.7Hz), 7.59(1H, s), 7.66 (1H, d, J=2.2Hz), 7.89(1H, t, J=1.1Hz) # Elementary Analysis Composition Formula Calcd. Found IR (cm⁻¹) Mass (EI) LR ((M + 2)+)502 NMR (ppm) (300 MHz, CD3OD) m.p. (° C.)

2.26-2.30(1H, br), 2.66-2.71(1H, br), 2.71(6H, s), 2.85(1H, t, J=12.6Hz), 2.96(3H, s), 3.38(1H, brd, J=17.3Hz), 3.48-3.58 (3H, brm), 3.66(1H, brt, J=12.9Hz), 3.77(1H, brd, J=12.6Hz), 4.23(1H, brd, J=17.9Hz), 6.59(1H, d, J=8.0Hz), 6.98(1H, brs), 7.03(1H, brd, J=7.7Hz), 7.12(1H, t, J=7.7Hz), 8.18(1H, brs), 8.24(1H, brs), 8.54(1H, brs) # Elementary Analysis Compostion Formula Calcd. Found IR (cm⁻¹) (neat) 3425, 2529, 1638, 1447 Mass

TABLE 56 NMR (ppm) (300 MHz, CDCl3) m.p. (° C.)

1.96(1H, dt, J=3.3, 12.6Hz), 2.10(1H, dt, J=1.9, 12.4Hz), 2.23 (1H, d, J=11.5Hz), 2.33(3H, s), 2.52-2.74(3H, m), 2.90(1H, dd, J=3.8, 11.0Hz), 3.02-3.26(3H, m), 3.63(3H, d, J=0.8Hz), 3.68(1H, d, J=16.5Hz), 6.51-6.57(1H, m), 7.01-7.07(3H, m), 7.16(1H, dd, J=2.7, 9.1Hz), 7.27(1H, dd, J=3.0, 8.5Hz), 7.63 (1H, s), 7.83(1H, dd, J=5.5, 9.3Hz) # Elementary Analysis Composition Formula Calcd. Found IR (cm⁻¹) Mass

1.91-2.00(1H, br), 2.16-2.22(2H, brm), 2.35(3H, s), 2.57-2.65(1H, brm), 2.73(1H, d, J=11.5Hz), 2.85(1H, t, J=11.8Hz), 2.93-3.19(4H, m), 3.58(1H, d, J=16.5Hz), 6.41-6.46(1H, m), 6.82-6.91(3H, m), 7.15(1H, dd, J=2.7, 9.1Hz), 7.20-7.28(1H, m), 7.66(1H, s), 7.73(1H, dd, J=5.2, 9.1Hz) # Elementary Analysis Composition Formula Calcd. Found IR (cm⁻¹) Mass (EI) LR (M+)362 NMR (ppm) (300 MHz, CD3OD) m.p. (° C.)

2.28-2.33(1H, br), 2.52(1H, brd, J=14.8Hz), 2.79-2.88(2H, brm), 2.88(3H, s), 3.17(1H, brd, J=16.2Hz), 3.29-3.69(6H, brm), 4.48(4H, s), 6.53(1H, d, J=6.9Hz), 6.92(1H, s), 6.93 (1H, d, J=6.9Hz), 7.04(1H, t, J=8.0Hz), 7.36-7.42(2H, br), 7.81-7.85(1H, br), 7.90-7.94(1H, br) # Elementary Analysis Composition Formula Calcd. Found IR (cm⁻¹) Mass

Example 1

Evaluation of Activity to Improve Learning and/or Memory Using Morris Water Maze

<Experiment Schedule>

In experiments, ICR male mice of 6 weeks old were used. Using Morris water maze as an experiment apparatus, ability of learning and memory of space was evaluated based on the latency until a mouse escapes to a platform arranged in a pool as an index. One trial was maximally 120 seconds, and 1 session was composed of three trials in which each mouse was made to swim in the pool from three different positions. Average time needed for the escape was calculated and evaluation was made based thereon. On the first day (the first session), no drug and nothing were administered. From the second session (Day 2), Compound 1, Compound 8 or a solvent was administered. Trial was repeated for 5 days (5 sessions).

The dose of Compound 1 was 10, 30 or 100 μg/kg, and the dose of Compound 8 was 100 μg/kg. Compound 1, Compound 8 or saline which was the solvent was subcutaneously administered 30 minutes before the first trial of each session. The data was subjected to analysis of variance and significance was evaluated according to Fisher's PLSD test. The cases where P<0.05 was evaluated as significant.

<Evaluation of Compound 1>

No difference in the time period required for escaping to the platform between the groups was observed in Session 1. With proceeding of the sessions, the time period required for the escaping to the platform was shortened in the group to which physiological saline was administered. On the other hand, as shown in FIG. 1, by administration of Compound 1, the time period required for the escaping to the platform was shortened dose-dependently from the second session, so that clear improvement in the ability of learning and memory of space was observed.

FIG. 1 shows the comparison between the learning process of the rats to which Compound 1 was administered and that of the rats to which saline was administered. In the graph, the ordinate indicates latency for reaching the plat form (and SE), and abscissa indicates the number of sessions (* means P<0.05, and ** means P<0.01). It was shown that ability of learning and memory of space was improved in the Morris water maze test by administration of Compound 1.

<Evaluation of Compound 8>

Similar to the evaluation of Compound 1, the latency required for escaping to the platform by mice was shortened by administration of Compound 8, and clear improvement in the ability of learning and memory of space was observed. FIG. 3 shows the comparison between the learning process of the rats to which Compound 8 was administered and that of the rats to which saline was administered.

Example 2

Effect for Improvement of Learning in Test of Learning of Step-Down Type Passive Avoidance

<Experiment Schedule>

In experiments, ICR male mice of 6 weeks old were used. The experiment apparatus comprised a plastic box sizing 25×25×30 cm (width×depth×height), a stainless steel grid for giving electrical shock, which was laid on the floor of the box, and a wooden platform sizing 4.5×4.5×3.0 cm (width×depth×height) placed on a corner on the floor grid.

Sixty minutes before the training trial, 100 or 300 μg/kg of Compound 1, or its solvent, saline, was subcutaneously administered. Thirty minutes later, 0.1 mg/kg of MK-801 which is a non-competitive antagonist of NMDA receptor, which is a compound that causes learning disability and/or memory disorder was intraperitoneally administered. Training trial was carried out by placing a mouse on the platform, and the time period until the mouse stepped down to the floor grid, that is, the Step-Down latency, was measured. Simultaneously with the attaching all of the feet of the mouse to the floor, an electrical shock of 0.6 mA was given for 2 seconds, thereby making the mouse to learn that an electrical shock would be given if the mouse would stepped down to the floor. Only the mice which showed the Step-Down latency of 3 to 30 seconds in the training trials were used in the test trials.

Test trials were carried out 24 hours after the training trials. Each mouse was again placed on the platform, and the Step-Down latency was measured for maximally 300 seconds.

<Evaluation of Compound 1>

The results are shown in FIG. 2. In the control group to which the solvent alone was administered, the Step-Down latency in the test trials was extended than that in the training trials, so that it was shown that the mice memorized that electrical shock was given when they stepped down to the floor. On the other hand, in the group to which MK-801 alone was administered, the Step-Down latency was significantly shorter than that of the control group, so that learning disability and memory disorder were induced. The action of shortening the Step-Down latency by MK-801 was significantly reduced by administration of Compound 1, so that it was observed that Compound 1 exhibited activity to improve the learning disability and memory disorder induced by MK-801.

FIG. 2 shows the Step-Down latency of the control group to which solvent alone was administered, the groups to which MK-801 was administered and of the groups to which Compound 1 was administered (the bar in each column is the median). In the group to which MK-801 was administered, the passive avoidance reaction was significantly suppressed when compared with the control group. This suppressant was recovered by administration of Compound 1, so that it was shown that Compound 1 had an activity to improve the learning disability and memory disorder induced by MK-801 (** means P<0.01 vs. the control, and ## means P<0.01 vs. the group to which MK-801 alone was administered).

Industrial Availability

The agent for improving learning and/or memory according to the present invention is useful for the therapy of dementia accompanying disorder of memory due to a cerebrovascular disease, neurodegererative disease such as Alzheimer's disease, endocrine disease, nutritional or metabolic disorder, infectious disease, drug addiction or the like. 

What is claimed is:
 1. A method for improving learning and/or memory in a subject which comprises administering to the subject an effective amount of an isoquinoline

derivative of the Formula (I): wherein R¹ represents hydrogen, C₁-C₅ alkyl, C₄-C₇ cycloalkylalkyl, C₅ -C₇ cycloalkenylalkyl, C₇ -C₁₄ aralkyl, C₄-C₅ transalkenyl, allyl, furanyl-2-ylalkyl, thienyl-2-ylalkyl, C₁-C₅ alkanoyl, benzoyl, vinyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl or C₈-C₁₄ arylalkanoyl; R² represents hydrogen or OR⁶ (wherein R⁶ represents hydrogen, C₁-C₅ alkyl or C₁-C₅ alkanoyl); R³ and R^(3′) independently represent C₁-C₅ alkyl, hydrogen, chlorine, fluorine, bromine, iodine, trifluoromethyl, cyano, hydroxy, C₁-C₃ alkoxycarbonyl, C₁-C₃ alkylcarbonylamino, C₁-C₅ alkoxy, nitro, amino, or C₁-C₃ alkylamino; R⁴ represents hydrogen, hydroxy, C₁-C₃ alkoxy, benzyl, or C₁-C₅ alkanoyl or halogen; X represents nitrogen or carbon; R⁵ exists only when X is carbon, and represents C₁-C₅ alkyl, hydrogen, chlorine, fluorine, bromine, iodine, trifluoromethyl, cyano, hydroxy, C₁-C₃ alkoxycarbonyl, C₁-C₃ alkylcarbonylamino, C₁-C₅ alkoxy, nitro, amino or C₁-C₃ alkylamino or a pharmaceutically acceptable salt thereof.
 2. The method for improving learning and/or memory according to claim 1, wherein in Formula (I), R¹ is hydrogen, methyl, ethyl, cyclopropylmethyl, allyl, phenethyl, furan-2-ylethyl or thiophene-2-ylethyl; R² is hydrogen, hydroxy, methoxy or ethoxy; R³ and R^(3′) independently are methyl, hydrogen, chlorine, fluorine, bromine, iodine, hydroxy, methoxy, nitro, amino or dimethylamino; R⁴ is hydrogen, hydroxy or methoxy; X is carbon; R⁵ is methyl, hydrogen, chlorine, fluorine, bromine, iodine, hydroxy, methoxy, nitro, amino or dimethylamino. 